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  1. Natto for Brain Health Too!
  2.  
  3. While investigating the potential brain health implications of eating soy-based natto alluded to by Michael, I came across some addition information, that not only suggests natto may not be bad for brain health, but might actually be downright good. Here is what I found.
  4.  
  5. Apparently Vitamin K2 (MK-7 form) isn't the only potential beneficial component of natto. Natto contains Nattokinase (henceforth referred to as NK), which is a serine protease, or in other words, an enzyme that cleaves protein bonds. Now obviously, cleaving proteins could be a good thing, or it could be a bad thing. But in the case of NK, it looks to be a good thing.
  6.  
  7. But first you might ask - don't ingested enzyme's get broken down in the digestive system? Why think NK would make it intact to the bloodstream from eating natto? The answer is found in study [1]. Short answer, in healthy human volunteers, a single dose of orally ingested NK, in softgel form, raised NK level in serum. NK level in the blood was elevated during a period from 2 to 24 hours post ingestion. The amount of purified NK in the single oral dose (2000 FU, or about 100mg NK) used in this study was about equivalent to amount of NK in 50g of natto. Based on unit conversion (from CU's to mg's) from studies [1] and [2], there is about 50mg of NK in the 25g of natto I eat per day.
  8.  
  9. So with that out of the way. What does NK do?
  10.  
  11. Apparently a heck of a lot. For a thorough discussion, with references, see these two extensive and very informative webpage on NK and this one too. A few excerpts from these two web pages:
  12. Heart disease
  13.  
  14. First, in addition to the artery calcification prevention benefit of MK-7 discussed in my first post, NK may be potentially useful as a clot-buster and blood thinner, There is quite a bit of evidence for its effectiveness in this regard[9][10][11][12][13][14][15][16][17]. Here is a typical result from amongst these studies [3], in which subjects were given a dose of NK equivalent to 50mg of natto:
  15.  
  16. As a result, D-dimer concentrations at 6, and 8 hours, and blood
  17. fibrin/fibrinogen degradation products at 4 hours after NK administration
  18. elevated significantly (p < 0.05, respectively). Factor VIII activity declined at
  19. 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was
  20. higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial
  21. thromboplastin time prolonged significantly at 2 and 4 hours following NK
  22. administration (p < 0.05 and p < 0.01, respectively). All the changes, however,
  23. were within the normal range. In conclusion, thus, a single-dose of NK
  24. administration appears enhancing fibrinolysis and anti-coagulation via several
  25. different pathways simultaneously.
  26.  
  27. But possible side effects have been reported. In one case report, a patient concurrently taking aspirin and 400 mg of nattokinase daily (equivalent to for seven consecutive days to prevent stroke suffered an acute cerebellar hemorrhage.[18]
  28.  
  29. Blood Pressure
  30.  
  31. One human intervention using nattokinase at an oral dose of 2,000 FU per capsule once daily (equiv to 50 g natto / day) for 8 weeks in persons with hypertension (n=86) noted that nattokinase was associated with a reduction in systolic blood pressure of 5.55mmHg (95% CI of 0.57-10.5mmHg reductions) and diastolic blood pressure by 2.84mmHg (95% CI of 0.33-5.33mmHg) with a decrease in renin activity by 1.17 ng/mL/h.
  32.  
  33. ---------
  34. [1] Altern Ther Health Med. 2013 May-Jun;19(3):16-9.
  35.  
  36. A pilot study on the serum pharmacokinetics of nattokinase in humans following a
  37. single, oral, daily dose.
  38.  
  39. Ero MP(1), Ng CM, Mihailovski T, Harvey NR, Lewis BH.
  40.  
  41.  
  42. CONTEXT: Nattokinase is a serine protease and is derived from natto, a
  43. traditional Japanese, fermented, soybean food meal. Multiple authors have
  44. described the significant fibrinolytic, antithrombotic, and antihypertensive
  45. effects of natto. Nattokinase has been growing in popularity for use as a dietary
  46. supplement for the benefit of cardiovascular health. Little is known regarding
  47. the pharmacokinetic and pharmacodynamic properties of this enzyme, and the
  48. bioavailability of nattokinase is currently unknown.
  49. OBJECTIVE: This study intended to (1) detect nattokinase directly and
  50. immunologically, (2) show that nattokinase and/or its metabolites were detectable
  51. in human blood following ingestion of a commercial preparation, and (3) chart a
  52. pharmacokinetic dosing effect for nattokinase.
  53. DESIGN: The research team designed the pilot study as an in vivo, human clinical
  54. trial. Healthy human subjects responded to an advertisement and were screened.
  55. Subjects who satisfied both inclusion and exclusion criteria were enrolled into
  56. the study. Subjects were then instructed to orally ingest a single capsule
  57. containing a known concentration of nattokinase immediately following a baseline
  58. blood draw. Subsequent blood draws occurred over a 24-h period.
  59. SETTING: This study was conducted in Oakland, California, at a clinical reference
  60. laboratory and was performed with the approval of an institutional review board
  61. (IRB) to ensure that appropriate ethical standards were met.
  62. PARTICIPANTS: Eleven healthy participants (five male, six female, ages 21-65),
  63. who met eligibility criteria, were enrolled.
  64. INTERVENTION(S): Administration of nattokinase occurred orally with the ingestion
  65. of a single daily dose (2000 FU) of nattokinase. Capsules, each containing
  66. approximately 100 mg of nattokinase, in softgel form (NSK-SD, Japan Bio Science
  67. Laboratory, Osaka, Japan), were used in the study.
  68. OUTCOME MEASURE(S): Baseline blood samples were collected, and participants were
  69. observed swallowing a single capsule of the nattokinase supplement before
  70. returning at 2, 4, 8, 12, 24, and 48 h post ingestion for subsequent blood draws.
  71. The presence of nattokinase in serum was measured by an enzyme-linked
  72. immunosorbent assay (ELISA), using a rabbit, polyclonal, antinattokinase-capture
  73. antibody. A pharmacokinetic pattern was observed for nattokinase between baseline
  74. and 48 h postdose.
  75. RESULTS: Peak serum levels of nattokinase were observed at approximately 13.3 h ±
  76. 2.5 h (mean ± standard error) postdose. Statistically significant increases in
  77. binding were detectable from baseline when comparing averaged data at time points
  78. t = 2 h-t = 24 h.
  79. CONCLUSIONS: These results provided the first evidence that nattokinase can be
  80. measured directly in the blood of humans. The results further suggest that a
  81. larger, more extensive, pharmacokinetic study of nattokinase is warranted.
  82. Additionally, looking for intact enzyme and bioactive nattokinase peptides should
  83. be a consideration for future studies investigating the pharmacokinetic profile
  84. of nattokinase.
  85.  
  86. PMID: 23709455
  87.  
  88. [2] Experientia. 1987 Oct 15;43(10):1110-1.
  89.  
  90. A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto; a
  91. typical and popular soybean food in the Japanese diet.
  92.  
  93. Sumi H(1), Hamada H, Tsushima H, Mihara H, Muraki H.
  94.  
  95. Author information:
  96. (1)Department of Physiology, Miyazaki Medical College, Japan.
  97.  
  98. A strong fibrinolytic activity was demonstrated in the vegetable cheese Natto,
  99. which is a typical soybean food eaten in Japan. The average activity was
  100. calculated at about 40 CU (plasmin units)/g wet weight. This novel fibrinolytic
  101. enzyme, named nattokinase, was easily extracted with saline. The mol. wt and pI
  102. were about 20,000 and 8.6, respectively. Nattokinase not only digested fibrin but
  103. also the plasmin substrate H-D-Val-Leu-Lys-pNA (S-2251), which was more sensitive
  104. to the enzyme than other substrates tried. Diisopropyl fluorophosphate and
  105. 2,2,2-trichloro-1-hydroxyethyl-o,o-dimethylphosphate strongly inhibited this
  106. fibrinolytic enzyme.
  107.  
  108. PMID: 3478223
  109.  
  110. -----------
  111. [3] Sci Rep. 2015 Jun 25;5:11601. doi: 10.1038/srep11601.
  112.  
  113. A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation
  114. profiles.
  115.  
  116. Kurosawa Y(1), Nirengi S(1), Homma T(1), Esaki K(2), Ohta M(3), Clark JF(4),
  117. Hamaoka T(1).
  118.  
  119. Our aim was to determine the quantitative effects of a single-dose of Nattokinase
  120. (NK) administration on coagulation/fibrinolysis parameters comprehensively in
  121. healthy male subjects. A double-blind, placebo-controlled cross-over NK
  122. intervention study was carried out in 12 healthy young males. Following the
  123. baseline blood draw, each subject was randomized to receive either a single-dose
  124. of 2,000 FU NK (NSK-SD, Japan Bio Science Laboratory Co., Ltd) or placebo with
  125. subsequent cross-over of the groups. Subjects donated blood samples at 2, 4, 6
  126. and 8 hours following administration for analysis of coagulation/fibrinolysis
  127. parameters. As a result, D-dimer concentrations at 6, and 8 hours, and blood
  128. fibrin/fibrinogen degradation products at 4 hours after NK administration
  129. elevated significantly (p < 0.05, respectively). Factor VIII activity declined at
  130. 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was
  131. higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial
  132. thromboplastin time prolonged significantly at 2 and 4 hours following NK
  133. administration (p < 0.05 and p < 0.01, respectively). All the changes, however,
  134. were within the normal range. In conclusion, thus, a single-dose of NK
  135. administration appears enhancing fibrinolysis and anti-coagulation via several
  136. different pathways simultaneously.
  137.  
  138. PMCID: PMC4479826
  139. PMID: 26109079
  140.  
  141. [9] Prevent Heart Attack and Stroke with Potent Enzyme that Dissolves Deadly Blood Clots in Hours. Health Sciences Institute, March 2002.
  142. [10] Maruyama M, Sumi H. Effect of Natto Diet on Blood Pressure. JTTAS, 1995
  143. [11] Sumi H, Hamada H, Nakanishi K, Hiratani H. Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinase. Acta Haematol 1990;84(3):139-43.
  144. [12] Sumi H, Hamada H, Mihara H. A novel strong fibrinolytic enzyme (nattokinase) in the vegetable cheese "natto." International Journal of Fibronolysis and Thrombolysis.
  145. [13] Abstracts of the ninth international congress on fibrinolysis, Amsterdam, 1988, Vol.2, Sup.1:67. 5.
  146. [15] Sumi H. Healthy Microbe "Bacillus natto". Japan Bio Science Laboratory Co. Ltd.
  147. [16] Sumi H. Structure and Fibronolytic Properties of Nattokinase.
  148. [17] Chang YY, Liu JS, Lai SL, Wu HS, Lan MY (2008). "Cerebellar hemorrhage provoked by combined use of nattokinase and aspirin in a patient with cerebral microbleeds". Intern. Med. 47 (5): 467–9. PMID 18310985.doi:10.2169/internalmedicine.47.0620.
  149. [18] Chang YY, Liu JS, Lai SL, Wu HS, Lan MY. Cerebellar hemorrhage provoked by combined use of nattokinase and aspirin in a patient with cerebral microbleeds. Intern Med . 2008;47(5):467-469.
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