9. Health benefits conferred by the constituents of Areca nut. Part-VI (Arecoline)

 

Arecoline is found to be the most important alkaloid among four major alkaloids and seven minor alkaloids found in areca nuts due to its role in modulating many physiological functions upon human consumption. Depending on the stage of maturity of areca nuts harvested, method of processing, geographical location and cultivar, its concentration can vary between 0.64 to 12.79 mg/g on dry weight basis.

In humans, depending on the dose and individual responsivity, arecoline causes enhanced alertness and learnability, enhanced mood, feeling of great pleasure, higher awakening, stimulation of the sexual desire, reduction in anxiety and promotion of calmness.

Arecoline is a very effective antiparasitic drug. Traditional Chinese Medicine uses three forms of processed areca nut (raw Arecae semen, Arecae semen tostum and Arecae semen carbonisata) for the preparation of antiparasitic drugs. Arecoline is found to be highly effective against tapeworms.

Arecoline has a wide spectrum of pharmacological effects beyond Central Nervous System such as modulation of cardiovascular, digestive and endocrine systems as well.  Like nicotine, arecoline also evokes addiction and withdrawal symptoms (upon discontinuation). Withdrawal symptoms could be mood swings, anxiety, irritability and insomnia.

The International Agency for Research on Cancer (IARC), an intergovernmental agency affiliated to WHO of the UN, published its report on the carcinogenic hazards of arecoline in 2021 (Vol. 128). About 20 experts drawn from 11 countries including India were part of the “working group”. After a thorough analysis, the working group concluded that “Arecoline is possibly carcinogenic to humans (Group 2B)”.

The working group came to a conclusion that arecoline exhibit multiple key characteristics of carcinogens in general. It alters DNA repair mechanism and causes genomic instability in experimental systems. However, the group found limited evidence for cancer in experimental animals. The group didn’t find any studies on the incidence of cancer due to the arecoline. Hence, with a greater degree of uncertainty, the working group concluded that arecoline might be a carcinogen. 

Many leading researchers are of the opinion that arecoline and related compounds have a considerable potential in medicine, with multiple positive neural effects that can be applied in neurology and psychiatry.

References:

IARC monograph published in 2021, Vol. 128.

Volgin et al. (2019). DARK Classics in Chemical Neuroscience: Arecoline. ACS Chemical Neuroscience, Vo. 10, pp. 2176-2185.

 

8. Health benefits conferred by the constituents of Areca nut. Part-V (Catechins)

 

Catechin, name was apparently derived from the word "catechu," a boiled extract/tannic juice of a Katch tree (Scientific name: Acacia catechu). This tree is called as “Kadira” in Sanskrit, “Khair” in Hindi. Kattha, a main product produced out of bark extract of Acacia catechu contains Catechins & its isomer epicatechin. As per an ancient Indian book, Jyotirnibandha written by Shivraj in AD 1524, Kattha (catechu extract) is a most important ingredient of Tambula (Betel quid) along with areca nut, betel leaf and lime. Apparently, the scientific name of Areca nut (Areca catechu) is derived due to the presence of large amount of catechin in Areca nuts. 

Catechin is one of the most abundant and important phenolic compounds found in areca nuts as well. Its concentration in areca nut depends upon the maturity of the areca nut harvested, processing method and the cultivars. The concentration can vary anywhere between 7 mg to 25 mg per gram of dried nuts.

Numerous studies involving cell-lines, animal models and in silico models have shown that Catechin/ epicatechin is a very important phytochemical. Its biological action encompasses antibacterial activity, anti-carcinogenic activity, anti-cataract activity, antifungal activity, anti-hypercholesterolemic activity, anti-inflammatory effect, anti-oxidative effect, antiproliferative activity, and antiviral activity. Though most studies relate their potential to anti-oxidative action and radical scavenging action, still the mechanism of action is not clearly understood. Recent studies shows that most of the beneficial functions of catechin/epicatechin is due to their ability to scavenge reactive oxygen species produced in the body, inhibiting transcription factors (controlling the expression of various genes in the body), and inhibition of pro-oxidant enzymes (tend to produce free-radicals in the body).

More than 18 clinical trials on the human population with different conditions have been carried out so far on the effectiveness of catechin /epicatechin. There is conclusive evidence that catechin / epicatechin are an effective and promising form of treatment of several disease conditions.

Most of the health benefits of Tea (Black & Green tea) is attributed to catechin/epicatechin & catechin gallates (gallic acid esters of catechins/epicatechins). Interestingly, areca nut contains considerable amount of catechins (7-25 mg/g) yet found little attention in scientific studies & food industries, which is rather surprising. 

References

Baranwal et al. (2022). Pharmacological Actions and Underlying Mechanisms of Catechin: A Review, Mini Reviews in Medicinal Chemistry, Vol. 22 (5), pp. 821-833(13).

7. Health benefits conferred by the constituents of Areca nut. Part-IV (Catechins)

 

Catechin is another very important phenolic substance present in areca nut in substantial quantity. Its concentration can range anywhere between 7-25 mg per gram of dry areca nut. The areca nuts of 6-7 months’ maturity were found to contain 24 mg of catechin, compared to the ripened areca nuts of  9-10 months’ maturity (8.51 mg/g) as per one Indonesian report. Interestingly, areca nuts harvested at 5 months maturity in China (Hainan province) for the production of Bing lang had only 7.2 mg per gram of dried areca nut, which is lesser than the matured areca nut.

Catechins are flavanols, which are also called proanthocyanidins or flavan-3-ols. Tea, wine and chocolates are some of the most prominent dietary suppliers of catechins to humans. Red wine, green, black and oolong teas, fruits like plum, apples, peach, strawberry and cherry, and beans and grains like broad bean, lentil and cocoa are rich in catechins. As per one study, Chocolate contributes 20% of the daily catechin intake in the Dutch population, and tea contributes 55%. Mediterranean diets, which are rich in wines and fresh fruits and vegetables, were found high in catechins. Mediterranean diet which is considered as one of the healthiest is found to provide about 100 mg of catechins and procyanidins per person per day.  Total catechin contents of green and black tea are about 420 and 250 mg/L, respectively.  About 12.5 grams of areca nut (Chali or white supari) or about 4 grams of red supari (Kempadike) can provide the equivalent amount of catechin to humans. 

Catechin are found to exhibit physiological effects, including antibacterial, antifungal, antiviral, antioxidative, and antitumor activities. Recent studies have suggested that catechins also promote oral health and contribute to a reduced risk for some systemic disease.

The oral cavity of humans contains more than hundred species of microbes. An increase in the number of these microorganisms like high pathogenic potential species, such as cariogenic and periodontopathic bacteria, and the change of microbial biota may result in, not only oral infection, but also systemic diseases, such as infective endocarditis and aspiration pneumonia. It is very important to control the growth of these microorganisms and its biota just after oral cleaning in order to suppress disease onset. Numerous studies have proved that catechin formulations inhibited the growth of the Actinomyces, periodontopathic bacteria and Candida strains tested, but did not inhibit that of the oral Streptococci that are important in the normal oral flora. Thus, it was clear that catechins can improve the oral hygiene and deter the onset of oral infection, and systemic diseases, such as infective endocarditis and aspiration pneumonia.

Perhaps, the ancient Indian medical practitioners were aware of the importance of catechin present in areca nut and hence had prescribed chewing of Tambula (Betel quid) after every meal.  

References

Tamura & Ochiai (2012) Exploring the possible applications of catechin (gel) for oral care of the elderly and disabled individuals, Japanese Dental Science Review, Vol. 48, pp. 126—134

Yusuf Yilmaz (2006). Novel uses of catechins in foods. Trends in Food Science & Technology, Vol. 17, pp. 64–71

Sari et al., (2020). Distinct phenolic, alkaloid and antioxidant profile in betel quid from four regions of Indonesia, Scientific Reports, Vol. 10 : 16254

Song et al., (2022). UHPLC-MS/MS identification, quantification of flavonoid compounds from Areca catechu L. extracts and in vitro evaluation of antioxidant and key enzyme inhibition properties involved in hyperglycemia and hypertension. Industrial Crops & Products. Vol. 189, pp. 115787.

 

6. Health benefits conferred by the constituents of Areca nut. Part-III (Arecatannins)

 

Tannins are an interesting class of polyphenols, believed to confer numerous health benefits. Tannins are categorized into two classes, namely, hydrolysable tannins and condensed tannins. Areca nut contains mainly condensed tannins which are having at least one monomer as catechin / epicatechin.   

Areca tannin is the main constituent of phenolic compounds found in areca nut. Its concentration can be as high as 40% by weight of the total phenolic content. It is made out of two epicatechin and one catechin molecules and hence categorized under condensed tannin group. 

Due to their complex structure, these tannins exhibit good antioxidant properties. Tannins can exert their function primarily at cellular but also physiological levels, presenting themselves as promising agents for preventing or treating several pathophysiological conditions. They exhibit important effects on cardiac well-being and inflammatory states. In addition, the antioxidant effect could also determine cascading effects that may prevent the growth of cancer cells. Tannins have the unique ability to complex with proteins. The interaction of tannin with proteins is one of the main mechanisms of biological activity of tannins.

Most consumed tannins can reach the colon almost intact, where the high molecular weight structures cannot be readily absorbed and must be further metabolized by the gut microbiota. The gut microbiota depolymerizes the condensed tannins and derivatize them into phenolic acids and valerolactones. Catechin and epicatechin can be readily absorbed in the proximal intestinal tract, while oligomer and polymer absorption rates decrease with increasing number of hydroxyl groups and molecular size.

Numerous research reports are showing that these tannins can help decrease the risk of cardiovascular and Alzheimer’s disease, delay cellular ageing, and maintain intestinal microbiota homeostasis. There are studies on their functions as molecules with pharmacological activity potentials, such as ROS (reactive oxygen species) reducing agent, anti-inflammatory, antifungal, antimicrobial, antiviral, anthelmintic, antimutagenic, and anticancer activities. Considering these health benefits, there is a serious contemplation to include tannins as “Nutraceuticals”.

References.

1.  Moura de Melo et al., (2023). Biological and pharmacological aspects of tannins and potential biotechnological applications, Food Chemistry, Vol. 414, 135645.

2.   Molino et al., (2023). Why is it important to understand the nature and chemistry of tannins to exploit their potential as nutraceuticals? Food Research International Vol. 173, 113329.

3.  Mugeri et al., (2022). Pharmacology and toxicology of tannins. Archives of Toxicology, Vol. 96, 1257–1277.

5. Health benefits conferred by the constituents of Areca nut. Part-II (Procyanidins)

 

B-type procyanidins are found to be one of the most abundant phenolic compounds found in Areca nuts. (–)-epicatechin is the most common monomeric unit of procyanidins. These procyanidins are also present in abundance in Cocoa, apples, grape seeds, and red wine.

These procyanidins have 20 times the antioxidant capacity of vitamin C and 50 times the antioxidant capacity of vitamin E. Procyanidins can neutralize the reactive oxygen species (ROS).

Several processes in our body, such as differentiation, metabolism, proliferation, and apoptosis, are maintained in a normal physiological state by our body’s endogenous antioxidative system. They keep the system in a state of dynamic redox equilibrium. Excessive production of reactive nitrogen species and reactive oxygen species (ROS) causes oxidative stress. Accumulation of ROS can trigger a cascade of reactions that causes direct damage to DNA, lipids, and proteins, ultimately leading to tissue dysfunction. Aside from that, ROS accumulation can contribute to the development of diseases, including cancers, neurodegenerative disorders, cardiovascular diseases, and metabolic disorders.

When the ROS level is low, it is usually advantageous and beneficial for cells and tissues, and normal rate of cell division, tissue repair, and angiogenesis happens without any interruption. Excessive ROS production disrupts multiple biomolecules, which can cause membrane damage. Furthermore, it will inactivate membrane receptors and enzymes, reduce membrane fluidity, increase membrane permeability to ions, and, in extreme cases, rupture the cell membrane and cell lysis leading to the cell death. In addition, lipid peroxides, nitric oxides, and superoxide radicals accumulate in cells and directly damage them by generating unstable radicals and interfering with natural antioxidant molecules and enzymes. Thus, high level of ROS causes apoptosis (programmed cell death), cell damage, DNA mutations, and cell death.

Procyanidin has been shown to prevent oxidative stress-induced DNA damage and promote DNA repair via various pathways. Furthermore, it is discovered that procyanidin could increase the expression and activity of antioxidant enzymes. One of the primary functions of antioxidants is to prevent apoptosis and reduce the level of ROS in cells. Procyanidins effectively does it.  Numerous researches have proved the beneficial effects of consumption of Cocoa, apples, grape seeds, and red wine and their ability to confer antioxidant property to the body. Procyanidins present in them is primarily responsible for the same. Interestingly, areca nut is one of the most abundant sources of procyanidins.

References

1.  Osakabe et al., (2023) Hormetic response to B-type procyanidin ingestion involves stress-related neuromodulation via the gut-brain axis: Preclinical and clinical observations, Frontier in Nutrition, DOI 10.3389/fnut.2022.969823.

2.   Dasiman et al., (2022) A Review of Procyanidin: Updates on Current Bioactivities and Potential Health Benefits, Biointerface Research in Applied Chemistry, Vol. 2 (5), pp. 5918 - 5940