Research and application of Nattokinase

Natto is a traditional fermented soybean food prevalent in Japan, which has a history of nearly 2000 years. In recent decades, natto has attracted worldwide attention because of its many prominent health functions. Natto has many physiological functions, such as anti-thrombosis, antihypertensive, antimicrobial, antioxidant, cancer prevention and so on. Nattokinase(NK), which has thrombolytic effect, is the most attractive active ingredient of natto. In 1987, the fibrinolytic activity of this protease was first discovered and introduced in this article by Sumi H et al. of Japan, which was named Nattokinase. Nattokinase has been introduced as raw material in many countries.
 
一. What is nattokinase?
Nattokinase(NK) is a protein kinase of Bacillus subtilis, a serine protease produced by Bacillus subtilis natto during natto fermentation. It is a natural active substance that can dissolve thrombus, regulate blood pressure and promote blood circulation.
 
Nattokinase stimulates vascular endothelial cells to produce tissue-type plasminogen activator (t-PA), which activates plasminogen into plasmin, dissolves fibrin and directly dissolves thrombus. At the same time, prourokinase is activated into urokinase in human body, and urokinase and t-PA activate plasminogen together to dissolve thrombus. Nattokinase can decompose thrombus directly. The thrombolytic effect of nattokinase per gram is equivalent to that of urokinase 1600IU. Nattokinase acts on thrombosis for 8-12 hours, while urokinase acts for only 30 minutes. Urokinase can only be injected, Nattokinase can be injected or taken orally.
二. Characteristics of Nattokinase

 
Nutritional components of natto:
Natto is rich in soybean phospholipids, saponins, oligosaccharides, crude polysaccharides, isoflavones, pyridine diphosphate, nattokinase, superoxide dismutase(SOD), protease, glucoamylase, cellulase, pectinase, amylase and other active enzymes produced by microbial fermentation.
 
Physicochemical characteristic:
1. There are 275 amino acids with molecular weight between 20,000 and 30,000.
2. The isoelectric point(pi) is 8.6±0.3(svensson Kawam method).
3. Stability: PH6-12 is stable at 60℃.
 
三. Historical sources of Nattokinase
According to literature, natto originated from Douchi in China and was brought to Japan by Jianzhen, a prominent monk in the Tang Dynasty. Every year, July 10 is named Natto Festival. Natto is know as the Japanese recipe for longevity.

In 1980, Japanese scientists Dr. Sumi HiroYuki’s “2:30 p.m. experiment” to discover the fibrinolytic substance Nattokinase (NK) in natto. The rate of dissolving artificial thrombus is 19 times faster than that of urokinase, acommonly used thrombolytic drug. Nattokinase is well-known for its similar functions with streptokinase, urokinase and other thrombolytic drugs, and has attracted worldwide attention for its great potential developing thrombolytic drugs. The Dr. Sumi HiroYuki is called “the father of nattokinase”.

Dr. Sumi H Shares the results of Nattokinase thrombolysis experiments

四. Relevant policies and standards of Nattokinase
 
1. National policy
In 2002, the Ministry of Heath clearly stipulated that “Natto has a certain edible history in China” in the “approved of Natto as a common food management”. Natto fermented by Bacillus subtilis should be managed according to common food. At present, there are four kinds of natto products on the market: fresh natto, natto capsule, natto compatible capsule and nattokinase capsule.
 
In  2004, the first Natto-based “National Food Health” health food was approved. There are 14 kinds of natto health food approved by the State Pharmaceutical Regulatory Bureau. Its function is to enhance immunity and assist in reducing blood lipid.
 
China’s Ministry of Commerce formulated the Natto Industry Standard in April 2009 and formally implemented it on December 01, 2009.
 
In 2014, The Sate Pharmaceutical Administration of China listed nattokinase as a functional component of health products, which was the first time that nattokinase was approved in China. The relevant reports are published in the 14^th edition of People’s Daily Overseas Edition on April 24, 2015.
 
In 2018, the formulation of China Nattokinase Group Standard initiated by China Health Association was officially launched.
 
The State Administration of Food and Drug Supervision approved nattokinase as the effective ingredient of natto health food, quantified it, standardized the testing standard, made the development of natto health food “rule-based”, enhanced the reliability and safety of natto health food, and pointed out the direction for the production of natto health food enterprises.
 
2. Content standards of Nattokinase:
According to the standard of Japan Nattokinase Association, The real nattokinase is a single-chain polypeptide serine protease with molecular weight of 27 KD composed of 275 amino acids, which has the function of decomposing fibrin. The content standard of nattokinase reached 20000FU/g of raw material and 2000FU/granule of finished product. The fibrinolytic activity of nattokinase raw materials on the international market is generally between 1000 and 40000FU/g.
 
3. Nattokinase content unit FU
On December 20, 2010, the authoritative organization of nattokinase, Japan Nattokinase Association, identified the standard unit of activity of nattokinase as "FU". It defines 1FU as the degradation product produced by the action of fibrin. The absorbance at 275 nm is calculated as 1 FU for every increase of 0.01 in the absorbance and blank of the sample.

五. Market situation of Nattokinase
It is understood that with the growing maturity of nattokinase research results, the market has gradually been opened up, and has now developed into the most potential health products raw materials and products. According to conservative estimates, Japan's annual sales of nattokinase health foods amount to billions of dollars. In addition, the United States, Europe and Canada and other developed countries have a considerable number of Nattokinase health food on the market. It is estimated that the global market capacity of nattokinase will be 15 billion US dollars, and the total sales capacity of our country will reach 19 billion RMB in the future.
 
六. Development prospects of Nattokinase
With the aggravation of the aging population and the younger trend of cardiovascular and cerebrovascular problems in China, the prevention of cardiovascular and cerebrovascular diseases has become a huge social health problem. Nattokinase, as a common preventive product of cardiovascular and cerebrovascular diseases in developed countries such as Japan and the United States, was approved by China in 2014, and has gradually entered the national vision since then.
 
At present, Japan, North Korea, South Korea, Taiwan and other countries and regions have launched a series of composite health products with nattokinase as the main functional component. The mean activity of nattokinase was 20,000 FU/g.
 
More than 10 large companies in Japan have produced a variety of products with nattokinase as the main ingredient. NKCP of Daiwa Pharmaceutical Company has been listed. NK capsules of U.S. International Medical and Health Technology Pharmaceutical Co., Ltd. have also been put on the market. Similar products are also available in Korea and North Korea. In China, the production technology of Nattokinase-Enkai capsule, a preparation of the Institute of Microbiology, Heilongjiang Academy of Sciences, has reached the pilot stage, and many oral medicines of Nattokinase have been put on the market, such as NATTO CAPSULE HEMO HEMATIC ENZYME of Herbage Pharmaceutical Co.,Ltd, Natto capsule of Yanjing Beer Co.,Ltd, Protein Selenium Natto capsule of Tianjin Baoheng Biotechnology Co,.Ltd, Nattokinase Capsules of Hunan Guishengfang, Nattokinase Capsules of Beijing Longxing, etc.
 
International Major Supplier Brands: BIOVEA(UK), Boostceuticals(US), Swanson Health Products(US), Nutraceutical Corporation(US), Dynamic Nutrition(US), NOW Foods(US), Doctor’s Best Inc.(US), Jarrow Formulas(US), Source Naturals(US), Pure Encapsulations(US), Healthy Origins(US).

七. Recommendation of Nattokinase Product Formula
Nattokinase can be compounded with other enzymes, such as bromelain, cellulase and amylase, or added with glycerol, beeswax and lecithin, DHA, SOD and other nutrients to make powder, tablets, soft and hard capsules, oral liquid or health food. Nattokinase can also be used with anise, angelica, bogbean, garlic, onion, Salvia miltiorrhiza, ginger, horse chestnut, turmeric, red clover, ginkgo biloba, white willow and so on.

八. Safety
Nattokinase is a new fibrinolytic compound. Nattokinase-rich natto is a promising functional food. Early epidemiology and clinical medicine indicated that the efficacy and safety of nattokinase can be used to treat many diseases, including hypertension, atherosclerosis, coronary heart disease (such as angina pectoris), stroke and peripheral vascular disease. Evidence from long-term heavy consumption in Japan suggests that nattokinase is safe and nutritious as an effective fibrinolytic agent.
 
1. Japanese Medical Tribune reported that "natto can prolong the life expectancy of familial hyperlipidemia patients by an average of 7 years".
2. The International Thrombosis Federation (ITA) announced that the long-term consumption of natto is one of the main reasons for Japanese longevity.
3. The American Heart Association (AHA) announced that many large studies have confirmed that nattokinase can reduce the mortality rate of patients with cardiovascular and cerebrovascular diseases by up to 30%.
4. People's Daily has reported in succession with the titles of "Magic Natto" and "Nattokinase Soluble Thrombosis". Natto has remarkable curative effect on cerebral thrombosis, myocardial infarction and other cardiovascular and cerebrovascular diseases.

九. Notes
1. Pregnant women are not recommended to eat. They should be suspended for 2 weeks before and after operation to avoid affecting wound healing.
2. Other diseases related to blood agglutination must consult a doctor before they can be eaten.
3. If there is a large amount of bleeding, such as rupture of blood vessels, accidents, etc. should also be avoided.
4. If patients with cerebral hemorrhage need to be 3 months after the onset of symptoms before they are suitable for consumption.
5. Nattokinase capsules belong to functional food and can not be substituted for drugs.
6. Not disturbed by gastric acid, it can be absorbed directly into the small intestine, and the action time in vivo is 8-12 hours.
7. Low calorie, low protein, obesity and nephropathy patients can safely eat.
8. It is not inconsistent with medicines and can reduce the adverse reactions of medicines.
9. No purine and vitamin K2, gout and warfarin patients can also eat it at ease.

十. Nattokinase of Yongyuan Bio
 
1. The characteristics of Yongyuan Bio nattokinase:

• High quality pure natto bacteria were used as raw materials, and Aspergillus niger was not used.
• Removal of vitamin K2
• Deodorization
• According to the activity analysis method promulgated by Japan Nattokinase Association
• The product has good water solubility.

Nattokinase produced by Shaanxi Yongyuan Bio-Tech Co., Ltd. is derived from traditional fermented food. It has simple production process, no side effects and high safety. It fully meets the requirements of drugs or food substrates for thrombosis treatment and can achieve the best effect by dissolving thrombus in vivo.
2. Specification and recommended dosage


3. Medical nutrition experts recommend the basic dosage of nattokinase for people taking Nattokinase.


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