Nattokinase: Solution to prevent and treat venous thrombosis

Natto, a fermented soybean product, has been consumed as a traditional food in Asian countries for thousands of years. Nattokinase (NK), a powerful clot-dissolving protein used to treat cardiovascular diseases (CVD), is produced by the bacterium Bacillus subtilis during the fermentation of soybeans to produce natto. NK has been widely studied in Japan, Korea, China and recently recognized by Western countries.

1. Ingredients of Natto

Natto is made from soybeans by the action of Bacillus subtilis var. natto (also known as Bacillus natto). In it, soybean is a general term for both black and green soybeans. There are three types of natto, including hamanatto, itohiki, and daitokuji natto. Itohiki natto is a natto that is inoculated with bacteria and cultured for 24 hours without the addition of salt. Daitokuji, or hamanatto, is made by injecting mold, growing for 4-6 months and adding salt.

Natto is a good source of protein (19g/serving), lipids (11g/serving), carbohydrates (5.4g fiber and 4.9g sugar), vitamins and minerals (vitamin C, iron, potassium, calcium) ). Natto also contains important active ingredients that promote heart health, especially Nattokinase.

2. Structure of Nattokinase

Nattokinase is a serine protease with a structure of a single polypeptide chain consisting of 275 amino acid residues, with a molecular weight of about 28 kDa.

NK is encoded by the aprN gene, which was first transcribed and sequenced from B. subtilis (natto). Because the amino acid sequence of NK is nearly identical (99.3% homologous) to Subtilisin E, NK is also considered a member of the subtilisin serine protease family. However, unlike subtilisin, NK has a very specific affinity for fibrinolysis.

3. Benefits of Nattokinase

Nattokinase is considered a safe, effective, low-cost and all-natural supplement for the treatment of heart disease and CVD. Animal and human trials have demonstrated that NK supports the circulatory system by thinning the blood and dissolving blood clots.

A mouse thrombosis model in the common carotid artery also demonstrated that the NK-treated mice restored 62% of arterial blood flow. Nattokinase exhibited significantly stronger thrombolytic activity than fibrinolytic enzymes, plasmin, or elastase (recovering 15% and 0% of carotid blood flow, respectively).

Nattokinase has been reported to affect both oxidative damage-mediated arterial thrombosis and inflammatory venous thrombosis. When ferric chloride (FeCl3) is introduced into damaged arteries, it leads to oxidative thrombosis and platelet adhesion.

However, after NK treatment, thrombus formation and platelet aggregation were inhibited. The effectiveness of NK is similar to that of the well-known blood thinner, aspirin. Unlike aspirin, which often causes bleeding or stomach ulcers, NK improves blood flow without any side effects.

Elevated levels of factors VII and VIII are associated with a higher risk of cardiovascular disease because these factors have the ability to trigger an episode of blood clotting.

In a human trial, three groups (healthy volunteers, patients with cardiovascular risk factors, and patients on dialysis) were given two NK capsules (2000 FU/tablet) daily. After two months, significant and similar reductions in both factor VII, factor VIII and fibrinogen were observed in all groups. No side effects were detected during the two-month trial and heart rate, body weight, and uric acid levels remained stable.

Nattokinase has a very strong ability to break down thrombus and fibrin. Even a single dose of NK has been reported to lead to fibrinolysis through cleavage of cross-linked fibrin. In that study, 12 healthy young men were randomized to receive an NK capsule (2000 FU). The results of this study indicate that multiple different pathways may be involved in the fibrinolytic and antiproliferative activities of NK.

Both NK and lumbrokinase (derived from earthworms), unlike most proteins, are resistant to the highly acidic gastric juices and can be absorbed in the later parts of the gastrointestinal tract. .

In 1995, Fujita and colleagues demonstrated that NK could be absorbed from the rat intestinal tract intact and that fibrinogen was degraded in plasma blood samples. Then, in 2013, a research team in the United States detected intact NK in the serum of healthy people after they were given a single dose of NK (2000 FU/100 mg) in a capsule.

The mechanism of nattokinase transport from the gastrointestinal tract to the systemic circulation remains to be elucidated. NK can withstand high temperatures (50°C) and pH (up to 10), which certainly contributes to this enzyme’s ability to keep intact in the gastrointestinal tract.

Currently, commercial imported products are widely used in Japan, China, Korea, European Union countries, Canada and the United States as a dietary supplement to thin the blood, prevent blood clots and improve blood circulation. Studies have also shown that NK can improve other diseases such as hypertension, stroke, Alzheimer’s disease, and atherosclerosis.

4. Nattokinase safety evaluation

Natto, a soybean product fermented by the bacterium Bacillus subtilis (natto), has been consumed as a traditional food in Japan for over a thousand years. Reports suggest that Natto contributes significantly to the longevity of the Japanese. Lipofusin (age pigment) accumulation is considered a sign of aging. In this regard, natto extract has been reported to slow lipofusin accumulation in the nematode, Caenorhabditis elegans. The lifespan of C. elegans is also significantly extended by Natto extract.

Although no adverse side effects were observed from the consumption of nattokinase in various human trials, including clinical trials, the safety profile of NK, including the effects of repeated doses, acute toxicity and genotoxicity, still need to be thoroughly addressed.

Comprehensive safety data, compiled by Good Laboratory Practice (GLP) compliance studies and reported in 2016, indicated that no clastogenic (chromosomal mutagenic) or mutagenic activity was observed in vitro after NK treatment.

B. subtilis, the bacteria responsible for natto production and NK synthesis, is not a pathogenic bacterium. Inoculation of natto-derived B. subtilis mice (1.51 × 10 9 CFU/mL) did not produce any signs of toxicity. Fourteen days after treatment, no viable B. subtilis cells were observed in the lung, liver, brain or kidney by histopathology.

No significant adverse events or mortality were observed in an acute toxicity study during the 14-day study period when rats were given a single dose of NK (2000 mg/kg). When rats received repeated daily doses of Nattokinase (1000 mg/kg) for 90 days, no abnormal clinical observations were detected compared with the control groups.

In human clinical studies, no-adverse-effect-level (NOAEL) was found when healthy volunteers consumed nattokinase (10 mg/kg) orally every day for 28 days. The study participants had no significant changes in urine output, blood pressure or pulse.

The overall data found in the toxicity studies provided a robust safety assessment for the use of Nattokinase for both regulators and pharmaceutical companies. Currently, the recommended use for NK is two tablets (100 mg/tablet) per day. This dose of Nattokinase raises very low toxicity concerns based on previously published safety studies.

References:

1. Weng Y, Yao J, Sparks S, Wang KY. Nattokinase: An Oral Antithrombotic Agent for the Prevention of Cardiovascular Disease. Int J Mol Sci. 2017 Feb 28;18(3):523. 
2. Afzaal M, Saeed F, Islam F, Ateeq H, Asghar A, Shah YA, et al. Nutritional Health Perspective of Natto: A Critical Review. Biochem Res Int. 2022 Oct 21;2022:5863887. 

Article source: Nutrition Research and Development Institute (https://inrd.vn/)

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