Monthly Archives: August 2017


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 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, 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.


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.

Polypodium leucotomos Extract Reduces Oxidative DNA Damage and Enhances DNA Repair

Polypodium leucatomos is an epiphytic fern native to tropical and subtropical regions of the Americas.  It’s alternative botanical name is Phlebodium aureum.

The common names for this fern include:

  • golden polypody
  • golden serpent fern
  • cabbage palm fern
  • gold-foot fern
  • hare-foot fern

Other common names in other languages include:

  • calaguala (Spanish language)
  • laua`e haole (Hawaiian)
  • samambaia (Portuguese)
  • hartassbräken (Swedish)

Image result for Polypodium leucotomos

Figure 1.  Polypodium leucotomos fern

Extracts from the Polypodium leucotomos fern have been used for centuries in South America and Spain, primarily for the treatment of:

  • psoriasis
  • various skin disorders
  • atopic dermatitis
  • vitiligo
  • sun protection from ultraviolet radiation

The phenolic components of Polypodium leucotomos extract include:  1

  • chlorogenic acid
  • coumaric acid
  • vanillic acid
  • caffeic
  • ferulic acid

Multiple Benefits From the Oral Supplementation of Polypodium leucotomos

A number of recent studies have demonstrated through their data that the oral administration of polypodium leucotomos postively effects health and affords the following photoprotective effects:  2

  • activates tumor suppressor p53
  • inhibits UV-induced Cox-2 expression
  • reduces inflammation
  • enhances the removal of UV-induced photoproducts, such as cyclobutane pyrimide dimers (CPDs)
  • reduces oxidative DNA damage and decreased UV-induced mutagenesis
  • reduces the number of 8-hydroxy-2’-deoxyguanosine-positive (8-OH-dG+) cells, which are markers of early DNA damage

Polypodium leucotomos Helps Prevent DNA Damage

Two studies from 2009 and 2010 suggest that Polypodium leucotomos helps prevent DNA damage before and during UV exposure. 3  4 

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

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

8-oxo-dG increases with age in DNA of mammalian tissues.  8-oxo-dG increases in both mitochonndrial DNA and nuclear DNA with age. 5

8-oxo-dG is a pre-mutagenic marker of oxidative damage to DNA and is caused by the UV-induced generation of reactive oxygen species. 8-oxo-dG positive cells were reduced by approximately 59% at 24 hours and by 79% at 48 hours in Polypodium leucotomos-treated animals compared to control animals.

These findings support the concept that Polypodium leucotomos reduces oxidative DNA damage.

Two weeks after UV exposure, mutations in Polypodium leucotomos-fed-mice were approximately 25% less than those from mice treated with UV alone.  6 

A clinical trial from 2010 found that a daily does of 240 mg of polypodium leucotomos by healthy volunteers aged 29 to 54 before UVA exposure decreased levels of a marker of DNA damage.  7 

Among the placebo volunteers a low dose of UV light produced a 217% increase in common DNA deletions.

Among the polypodium leucotomos supplemented volunteers showed a corresponding 84% decrease in common DNA deletions.  8 

When the UV exposure was increased the common DNA deletions increased by 760% for the placebo volunteers, whereas in the polypodium leucotomos volunteers there was only an increase of 61%.  9  

Polypodium Leucotomos Extract: A Photoprotective Anti Aging Oral Supplement

Intensify Sulforaphane Formation in Cooked Cruciferous Vegetables By Using Mustard Seed Powder


Glucosinolates are natural components of many pungent plants that occur as secondary metabolites of most of the Brassicales family, or the cruciferous vegetables.   When these vegetables are chewed, a pungent taste arises due to the breakdown products of glucosinolates.

There are a number of vegetables, sprouts and seeds that contain glucosinolates.  Table I below is a comprehensive list:

Table 1:  Vegetables, sprouts and seeds containing Glucosinolates








Chinese cabbage












Brussel sprouts


Broccoli sprouts






Bok choy




Daikon radish






Maca root


Mustard greens






Mustard seeds



Each vegetable, sprout and seed usually contains more than one glucosinolate.  However, certain vegetables, sprouts and seeds may contain a predominant amount of one glucosinolate.  An example is the following:

  • Broccoli and broccoli sprouts contain large amounts of glucoraphanin
  • Mustard seeds and Brussel sprouts contain a large amount of Sinigrin
  • Garden cress and cabbage contain a large amount of glucotropaeolin
  • Watercress contains a large amount of gluconasturtiin

The total number of documented glucosinolates from nature can be estimated to around 132, as of 2011.  1  For purposes of this article, we will focus on the 4 most important glucosinolates and the ones that have been the subject of the majority of medical research.  These 4 glucosinolates include:

  • Gluconasturtiin
  • Glucoraphanin
  • Glucotropaeolin
  • Sinigrin

Gluconasturtiin, also known as phenethylglucosinolate, is a widely distributed glucosinolate in cruciferous vegetables.  The name is derived from it occurrence in watercress which has the botanical name Nasturtium officinale.

Glucoraphanin is a glucosinolate distributed in broccoli, Brussel sprouts, cabbage and cauliflower.  It is also found in large amounts in young sprouts of cruciferous vegetables, like broccoli sprouts.

Glucotropaeolin is a phytochemical from Tropaeolum majus, which is commonly known as garden nasturtium, Indian cress or monks cress.  It is also found in cabbage.

Sinigrin is widely distributed in the plants of the Brassicaceae such as Brussel sprouts, broccoli, horseradish and black mustard seeds.

Table 2 below lists the various foods and the corresponding glucosinolate content.

Table 2. Glucosinolate Content of Selected Cruciferous
Brussels sprouts ½ cup (44 g)  
Garden cress ½ cup (25 g)  
Mustard greens ½ cup, chopped (28 g)  
Turnip ½ cup, cubes (65 g)  
Cabbage, savoy ½ cup, chopped (45 g)  
Kale 1 cup, chopped (67 g)  
Watercress 1 cup, chopped (34 g)  
Kohlrabi ½ cup, chopped (67 g)  
Cabbage, red ½ cup, chopped (45 g)  
Broccoli ½ cup, chopped (44 g)  
Horseradish 1 tablespoon (15 g)  
Cauliflower ½ cup, chopped (50 g)  
Bok choy (pak choi) ½ cup, chopped (35 g)  

Source:  Linus Pauling Institute Micronutrient Information Center –  Isothiocyanates


Each of the vegetables, sprouts and seeds contain the enzyme myrosinase, which is activated when the vegetable, sprout or seeds is damaged (chopped or chewed) in the presence of water.  The glucosinolate converts to an isothiocyanate (or thiocyanate) through the enzymatic activity of myrosinase.  These isothiocyanates are the defensive substances of the plant.

Thus glucosinolates are the precursors to isothiocyanates through the breakdown of the enzyme myrosinase.  Myrosinase activity on the glucosinolate also continues in the gastrointestinal tract through intestinal bacteria which allows for some further formation and absorption of isothiocyanates. 2

Image result for glucosinolates myrosinase pathway

Figure 1:  Glucosinolates Hydrolysis by Myrosinase  (Source:  Linus Pauling Institute – Isothiocyanates)


Sulforaphane is obtained from cruciferous vegetables such as broccoli, broccoli sprouts, Brussels sprouts, and cabbages. It is produced when the enzyme myrosinase transforms glucoraphanin into sulforaphane upon damage to the plant (such as from chewing), which allows the two compounds to mix and react. 

When cruciferous vegetables are cooked, by either boiling in water, baking, frying or steamed, it prevents the formation of any significant levels of sulforaphane due to the heat inactivating the myrosinase enzyme.

However, the addition of powdered mustard seeds to the heat processed (cooked) cruciferous vegetables significantly increases the formation of sulforaphane.  3 

The best way to add mustard seed powder is to grind mustard seeds, in a spice grinder, instead of using pre-powdered mustard seeds.  This way you do not use mustard seed powder that has oxidized oils by sitting on the market shelf.

It has also been found that daikon radish added to cruciferous vegetables supports the formation of sulforaphane, even when the daikon radish is heated at 125 °C for 10 min.  4  

Second Strategy to Cooking

Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More

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.


Green perilla leaf


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.


Perilla seeds


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.


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). 


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. 


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.


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).


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

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
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
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
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


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