AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Food Science and Human Wellness Article
PDF (1.4 MB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Open Access

Nattokinase as a functional food ingredient: therapeutic applications and mechanisms in age-related diseases

Hao Wua, Qian Zhanga, Hao Suob, Feng Xuc, Wanxu Huanga,d,e( ), Dan Ohtan Wanga,f,g( )
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
College of Optoelectronic Engineering, and Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen 518060, China
College of Life Sciences and Biopharmaceutical, Shenyang Pharmaceutical University, Shenyang 110016, China
The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, China
State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang 222001, China
RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan

Peer review under responsibility of Tsinghua University Press.

Show Author Information

Graphical Abstract

Abstract

Consumption of natto, a traditional eastern Asian food made of fermented soybeans by Bacillus subtilis, has long been linked to healthy aging and longer human lifespan. As the key thrombolytic ingredient of natto, the serine protease nattokinase (NK) has been developed into a widely-used dietary supplement. NK has shown excellent anti-thrombus, thrombolytic, and anti-inflammation activities that potentially delay aging and provide therapeutic effects on aging-related diseases. In this review, we critically overview the experimental and clinical evidence in the past 20 years that support the beneficial function of NK in the prevention and treatment of aging-related diseases, including cardiovascular diseases, Alzheimer’s disease, other abnormalities and cancer. We focus on the underlying molecular mechanisms and recent advances in application methods that are aimed at further development of NK for healthier aging of modern society. The challenges and unsolved issues in this area are also discussed.

Keywords

NattokinaseFunctional food ingredientAging-related diseasesCardiovascular diseasesInflammation

References

[1]

D. Melzer, L.C. Pilling, L. Ferrucci, The genetics of human ageing, Nat. Rev. Genet. 21 (2020) 88-101. https://doi.org/10.1038/s41576-019-0183-6.
Crossref Google Scholar
[2]

J. Luo, K. Mills, S. le Cessie, et al., Ageing, age-related diseases and oxidative stress: what to do next? Ageing Res. Rev. 57 (2020) 100982. https://doi.org/10.1016/j.arr.2019.100982.
Crossref Google Scholar
[3]

J. Campisi, P. Kapahi, G.J. Lithgow, et al., From discoveries in ageing research to therapeutics for healthy ageing, Nature 571 (2019) 183-192. https://doi.org/10.1038/s41586-019-1365-2.
Crossref Google Scholar
[4]

A. Arafa, Y. Kokubo, R. Kashima, et al., The lifelong health support 10: a Japanese prescription for a long and healthy life, Environ. Health Prev. Med. 27 (2022) 23. https://doi.org/10.1265/EHPM.22-00085.
Crossref Google Scholar
[5]

C. Nagata, K. Wada, T. Tamura, et al., Dietary soy and natto intake and cardiovascular disease mortality in Japanese adults: the Takayama study, Am. J. Clin. Nutr. 105 (2017) 426-431. https://doi.org/10.3945/ajcn.116.137281.
Crossref Google Scholar
[6]

H. Chen, E.M. McGowan, N. Ren, et al., Nattokinase: a promising alternative in prevention and treatment of cardiovascular diseases, Biomark. Insights. 13 (2018) 1177271918785130. https://doi.org/10.1177/1177271918785130.
Crossref Google Scholar
[7]

T. Li, C. Zhan, G. Guo, et al., Tofu processing wastewater as a low-cost substrate for high activity nattokinase production using Bacillus subtilis, BMC Biotechnol. 21 (2021) 57. https://doi.org/10.1186/s12896-021-00719-1.
Crossref Google Scholar
[8]

Y. Li, L.Q. Chen, X.Y. Tang, et al., Biotechnology, bioengineering and applications of Bacillus nattokinase, Biomolecules 12 (2022) 980. https://doi.org/10.3390/biom12070980.
Crossref Google Scholar
[9]

J. Liu, J. Xing, T. Chang, et al., Purification of nattokinase by reverse micelles extraction from fermentation broth: effect of temperature and phase volume ratio, Bioprocess Biosyst. Eng. 28 (2006) 267-273. https://doi.org/10.1007/s00449-005-0032-1.
Crossref Google Scholar
[10]

R. Garg, B.N. Thorat, Nattokinase purification by three phase partitioning and impact of t-butanol on freeze drying, Sep. Purif. Technol. 131 (2014) 19-26. https://doi.org/10.1016/j.seppur.2014.04.011
Crossref Google Scholar
[11]

D. Li, L. Hou, M. Hu, et al., Recent advances in nattokinase-enriched fermented soybean foods: a review, Foods 11 (2022) 1867. https://doi.org/10.3390/foods11131867.
Crossref Google Scholar
[12]

T. Nakamura, Y. Yamagata, E. Ichishima, Nucleotide sequence of the subtilisin NAT gene, aprN, of Bacillus subtilis (natto), Biosci. Biotechnol. Biochem. 56 (1992) 1869-1871. https://doi.org/10.1271/bbb.56.1869.
Crossref Google Scholar
[13]

T.T. Nguyen, T.D. Quyen, H.T. Le, Cloning and enhancing production of a detergent- and organic-solvent-resistant nattokinase from Bacillus subtilis VTCC-DVN-12-01 by using an eight-protease-gene-deficient Bacillus subtilis WB800, Microb. Cell Fact. 12 (2013) 1. https://doi.org/10.1186/1475-2859-12-79.
Crossref Google Scholar
[14]

U. Shinde, M. Inouye, Folding mediated by an intramolecular chaperone: autoprocessing pathway of the precursor resolved via a substrate assisted catalysis mechanism, J. Mol. Biol. 247 (1995) 390-395. https://doi.org/10.1006/jmbi.1994.0147.
Crossref Google Scholar
[15]

Y. Jia, H. Liu, W. Bao, et al., Functional analysis of propeptide as an intramolecular chaperone for in vivo folding of subtilisin nattokinase, FEBS Lett. 584 (2010) 4789-4796. https://doi.org/10.1016/j.febslet.2010.11.011.
Crossref Google Scholar
[16]

Y. Jia, X. Cao, Y. Deng, et al., Four residues of propeptide are essential for precursor folding of nattokinase, Acta Biochim. Biophys. Sin. (Shanghai) 46 (2014) 957-964.
Crossref Google Scholar
[17]

Y. Peng, X. Yang, Y. Zhang, Microbial fibrinolytic enzymes: an overview of source, production, properties, and thrombolytic activity in vivo, Appl. Microbiol. Biotechnol. 69 (2005) 126-132. https://doi.org/10.1007/s00253-005-0159-7.
Crossref Google Scholar
[18]

S. Wu, C. Feng, J. Zhong, et al., Roles of s3 site residues of nattokinase on its activity and substrate specificity, J. Biochem. 142 (2007) 357-364. https://doi.org/10.1093/jb/mvm142.
Crossref Google Scholar
[19]

R. Kapoor, S. Khowal, B.P. Panda, et al., Comparative genomic analyses of Bacillus subtilis strains to study the biochemical and molecular attributes of nattokinases, Biotechnol. Lett. 44 (2022) 485-502. https://doi.org/10.1007/s10529-022-03226-1.
Crossref Google Scholar
[20]

Z. Zheng, M. Ye, Z. Zuo, et al., Probing the importance of hydrogen bonds in the active site of the subtilisin nattokinase by site-directed mutagenesis and molecular dynamics simulation, Biochem. J. 395 (2006) 509-515. https://doi.org/10.1042/BJ20050772.
Crossref Google Scholar
[21]

Z. Zheng, Z. Zuo, Z. Liu, et al., Construction of a 3D model of nattokinase, a novel fibrinolytic enzyme from Bacillus natto. a novel nucleophilic catalytic mechanism for nattokinase, J. Mol. Graph. Model. 23 (2005) 373-380. https://doi.org/10.1016/j.jmgm.2004.10.002.
Crossref Google Scholar
[22]

J. Ren, Y. Zhang, Targeting autophagy in aging and aging-related cardiovascular diseases, Trends Pharmacol. Sci. 39 (2018) 1064-1076. https://doi.org/10.1016/j.tips.2018.10.005.
Crossref Google Scholar
[23]

H. Sumi, H. Hamada, K. Nakanishi, et al., Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinase, Acta Haematol. 84 (1990) 139-143. https://doi.org/10.1159/000205051.
Crossref Google Scholar
[24]

M. Fujita, K. Hong, Y. Ito, et al., Thrombolytic effect of nattokinase on a chemically induced thrombosis model in rat, Biol. Pharm. Bull. 18 (1995) 1387-1391.
Crossref Google Scholar
[25]

J. Xu, M. Du, X. Yang, et al., Thrombolytic effects in vivo of nattokinase in a carrageenan-induced rat model of thrombosis, Acta Haematol. 132 (2014) 247-253. https://doi.org/10.1159/000360360.
Crossref Google Scholar
[26]

S. Kamiya, M. Hagimori, M. Ogasawara, et al., In vivo evaluation method of the effect of nattokinase on carrageenan-induced tail thrombosis in a rat model, Acta Haematol. 124 (2010) 218-224. https://doi.org/10.1159/000321518.
Crossref Google Scholar
[27]

H. Sumi, Y. Yanagisawa, C. Yatagai, et al., Natto Bacillus as an oral fibrinolytic agent: nattokinase activity and the ingestion effect of Bacillus subtilis natto, Food Sci. Technol. Res. 10 (2004) 17-20.
Crossref Google Scholar
[28]

J. Jang, T.S. Kim, J. Cai, et al., Nattokinase improves blood flow by inhibiting platelet aggregation and thrombus formation, Lab. Anim. Res. 29 (2013) 221. https://doi.org/10.5625/lar.2013.29.4.221.
Crossref Google Scholar
[29]

Y. Kurosawa, S. Nirengi, T. Homma, et al., A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles, Sci. Rep. 5 (2015) 11601. https://doi.org/10.1038/srep11601.
Crossref Google Scholar
[30]

M.R. Cesarone, G. Belcaro, A.N. Nicolaides, et al., Prevention of venous thrombosis in long-haul flights with Flite Tabs: The LONFLIT-FLITE randomized, controlled trial, Angiology 54 (2003) 531-539. https://doi.org/10.1177/000331970305400502.
Crossref Google Scholar
[31]

J. Le Blanc, M. Lordkipanidzé, Platelet function in aging, Front. Cardiovasc. Med. 6 (2019) 109. https://doi.org/10.3389/fcvm.2019.00109.
Crossref Google Scholar
[32]

H.J. Yoo, M. Kim, M. Kim, et al., The effects of nattokinase supplementation on collagen-epinephrine closure time, prothrombin time and activated partial thromboplastin time in nondiabetic and hypercholesterolemic subjects, Food Funct. 10 (2019) 2888-2893. https://doi.org/10.1039/c8fo02324g.
Crossref Google Scholar
[33]

H. Sumi, H. Hamada, H. Tsushima, et al., A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto; a typical and popular soybean food in the Japanese diet, Experientia. 43 (1987) 1110-1111. https://doi.org/10.1007/BF01956052.
Crossref Google Scholar
[34]

H. Wu, H. Wang, W. Li, et al., Nattokinase-heparin exhibits beneficial efficacy and safety-an optimal strategy for CKD patients on hemodialysis, Glycoconj. J. 36 (2019) 93-101. https://doi.org/10.1007/s10719-019-09860-8.
Crossref Google Scholar
[35]

C. Yatagai, M. Maruyama, T. Kawahara, et al., Nattokinase-promoted tissue plasminogen activator release from human cells, Pathophysiol. Haemost. Thromb. 36 (2008) 227-232. https://doi.org/10.1159/000252817.
Crossref Google Scholar
[36]

T. Urano, H. Ihara, K. Umemura, et al., The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis cleaves and inactivates plasminogen activator inhibitor type 1, J. Biol. Chem. 276 (2001) 24690-24696. https://doi.org/10.1074/jbc.M101751200.
Crossref Google Scholar
[37]

D.E. Vaughan, R. Rai, S.S. Khan, et al., Plasminogen activator inhibitor-1 is a marker and a mediator of senescence, Arterioscler. Thromb. Vasc. Biol. 37 (2017) 1446-1452. https://doi.org/10.1161/ATVBAHA.117.309451.
Crossref Google Scholar
[38]

R.P. Tracy, A.M. Arnold, W. Ettinger, et al., The relationship of fibrinogen and factors Ⅶ and Ⅷ to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study, Arterioscler. Thromb. Vasc. Biol. 19 (1999) 1776-1783. https://doi.org/10.1161/01.atv.19.7.1776.
Crossref Google Scholar
[39]

C.H. Hsia, M.C. Shen, J.S. Lin, et al., Nattokinase decreases plasma levels of fibrinogen, factor Ⅶ, and factor Ⅷ in human subjects, Nutr. Res. 29 (2009) 190-196. https://doi.org/10.1016/j.nutres.2009.01.009.
Crossref Google Scholar
[40]

Y. Wang, H. Wang, Y. Zhang, et al., Stepwise strategy to identify thrombin as a hydrolytic substrate for nattokinase, J. Chem. Inf. Model. 62 (2022) 5780-5793. https://doi.org/10.1021/acs.jcim.2c00978.
Crossref Google Scholar
[41]

B. Bora, D. Gogoi, D. Tripathy, et al., The N-terminal-truncated recombinant fibrin(ogen)olytic serine protease improves its functional property, demonstrates in vivo anticoagulant and plasma defibrinogenation activity as well as pre-clinical safety in rodent model, Int. J. Biol. Macromol. 111 (2018) 462-474. https://doi.org/10.1016/j.ijbiomac.2017.12.140.
Crossref Google Scholar
[42]

L. Bencivenga, P. de Souto Barreto, Y. Rolland, et al., Blood pressure variability: a potential marker of aging, Ageing Res. Rev. 80 (2022) 101677. https://doi.org/10.1016/j.arr.2022.101677.
Crossref Google Scholar
[43]

B.H. Lee, Y.S. Lai, S.C. Wu, Antioxidation, angiotensin converting enzyme inhibition activity, nattokinase, and antihypertension of Bacillus subtilis (natto)-fermented pigeon pea, J. Food Drug Anal. 23 (2015) 750-757. https://doi.org/10.1016/j.jfda.2015.06.008.
Crossref Google Scholar
[44]

M. Fujita, K. Ohnishi, S. Takaoka, et al., Antihypertensive effects of continuous oral administration of nattokinase and its fragments in spontaneously hypertensive rats, Biol. Pharm. Bull. 34 (2011) 1696-1701. https://doi.org/10.1248/bpb.34.1696.
Crossref Google Scholar
[45]

J.Y. Kim, S.N. Gum, J.K. Paik, et al., Effects of nattokinase on blood pressure: a randomized, controlled trial, Hypertens. Res. 31 (2008) 1583-1588. https://doi.org/10.1291/hypres.31.1583.
Crossref Google Scholar
[46]

G.S. Jensen, M. Lenninger, M.P. Ero, et al., Consumption of nattokinase is associated with reduced blood pressure and von willebrand factor, a cardiovascular risk marker: Results from a randomized, double-blind, placebo-controlled, multicenter north american clinical trial, Integr. Blood Press. Control 9 (2016) 95-104. https://doi.org/10.2147/IBPC.S99553.
Crossref Google Scholar
[47]

K. Murakami, N. Yamanaka, K. Ohnishi, et al., Inhibition of angiotensin I converting enzyme by subtilisin NAT (nattokinase) in natto, a Japanese traditional fermented food, Food Funct. 3 (2012) 674-678. https://doi.org/10.1039/c2fo10245e.
Crossref Google Scholar
[48]

S.M. Keziah, C.S. Devi, Fibrinolytic and ACE inhibitory activity of nattokinase extracted from Bacillus subtilis VITMS 2: a strain isolated from fermented milk of Vigna unguiculata, Protein J. 40 (2021) 876-890. https://doi.org/10.1007/s10930-021-10023-8.
Crossref Google Scholar
[49]

H. Chen, J. Chen, F. Zhang, et al., Effective management of atherosclerosis progress and hyperlipidemia with nattokinase: a clinical study with 1062 participants, Front. Cardiovasc. Med. 9 (2022) 964977. https://doi.org/10.3389/fcvm.2022.964977.
Crossref Google Scholar
[50]

N.N. Ren, H.J. Chen, Y. Li, et al., A clinical study on the effect of nattokinase on carotid artery atherosclerosis and hyperlipidaemia, Zhonghua Yi Xue Za Zhi 97 (2017) 2038-2042. https://doi.org/10.3760/cma.j.issn.0376-2491.2017.26.005.
Crossref Google Scholar
[51]

S.J. Kang, Y. Lim, A.J. Kim, Korean red ginseng combined with nattokinase ameliorates dyslipidemia and the area of aortic plaques in high cholesterol-diet fed rabbits, Food Sci. Biotechnol. 23 (2014) 283-287. https://doi.org/10.1007/s10068-014-0039-y.
Crossref Google Scholar
[52]

H.N. Hodis, W.J. Mack, H.J. Meiselman, et al., Nattokinase atherothrombotic prevention study: a randomized controlled trial, Clin. Hemorheol. Microcirc. 78 (2021) 339-353. https://doi.org/10.3233/CH-211147.
Crossref Google Scholar
[53]

A.J. Lusis, Atherosclerosis, Nature 407 (2000) 233-241. https://doi.org/10.1038/35025203.
Crossref Google Scholar
[54]

X. Pan, P. Liang, L. Teng, et al., Study on molecular mechanisms of nattokinase in pharmacological action based on label-free liquid chromatography–tandem mass spectrometry, Food Sci. Nutr. 7 (2019) 3185-3193. https://doi.org/10.1002/fsn3.1157.
Crossref Google Scholar
[55]

P.P. Toth, S. Fazio, N.D. Wong, et al., Risk of cardiovascular events in patients with hypertriglyceridaemia: a review of real-world evidence, Diabetes. Obes. Metab. 22 (2020) 279-289. https://doi.org/10.1111/dom.13921.
Crossref Google Scholar
[56]

N. C. Yang, C. W. Chou, C. Y. Chen, et al., Combined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia, Asia Pac. J. Clin. Nutr. 18 (2009) 310-317.
Google Scholar
[57]

D.J. Wu, C.S. Lin, M.Y. Lee, Lipid-lowering effect of nattokinase in patients with primary hypercholesterolemia, Acta Cardiol. Sin. 25 (2009) 26-30.
Google Scholar
[58]

Y. Wang, X. Ji, R.K. Leak, et al., Stem cell therapies in age-related neurodegenerative diseases and stroke, Ageing Res. Rev. 34 (2017) 39-50. https://doi.org/10.1016/j.arr.2016.11.002.
Crossref Google Scholar
[59]

J.M. Wang, H.Y. Chen, S.M. Cheng, et al., Nattokinase reduces brain infarction, fibrinogen and activated partial thromboplastin time against cerebral ischemia-reperfusion injury, J. Food Drug Anal. 20 (2012) 686-691.
Google Scholar
[60]

P.T. Pham, B. Han, B.X. Hoang, Nattospes as effective and safe functional supplements in management of stroke, J. Med. Food 23 (2020) 879-885. https://doi.org/10.1089/jmf.2019.0183.
Crossref Google Scholar
[61]

H. Ji, L. Yu, K. Liu, et al., Mechanisms of nattokinase in protection of cerebral ischemia, Eur. J. Pharmacol. 745 (2014) 144-151. https://doi.org/10.1016/j.ejphar.2014.10.024.
Crossref Google Scholar
[62]

N.N. Fadl, H.H. Ahmed, H.F. Booles, et al., Serrapeptase and nattokinase intervention for relieving Alzheimer’s disease pathophysiology in rat model, Hum. Exp. Toxicol. 32 (2013) 721-735. https://doi.org/10.1177/0960327112467040.
Crossref Google Scholar
[63]

H. Hampel, J. Hardy, K. Blennow, et al., The amyloid-β pathway in Alzheimer’s disease, Mol. Psychiatry. 26 (2021) 5481-5503. https://doi.org/10.1038/s41380-021-01249-0.
Crossref Google Scholar
[64]

S.K. Metkar, A. Girigoswami, D.D. Bondage, et al., The potential of lumbrokinase and serratiopeptidase for the degradation of Aβ 1-42 peptide-an in vitro and in silico approach, Int. J. Neurosci. (2022) 1-12.
Crossref Google Scholar
[65]

R.L. Hsu, K.T. Lee, J.H. Wang, et al., Amyloid-degrading ability of nattokinase from Bacillus subtilis natto, J. Agric. Food Chem. 57 (2009) 503-508. https://doi.org/10.1021/jf803072r.
Crossref Google Scholar
[66]

S.K. Metkar, A. Girigoswami, R. Murugesan, et al., In vitro and in vivo insulin amyloid degradation mediated by Serratiopeptidase, Mater. Sci. Eng. C. 70 (2017) 728-735.
Crossref Google Scholar
[67]

P.C. Bhatt, A. Verma, F.A. Al-Abbasi, et al., Development of surface-engineered PLGA nanoparticulate-delivery system of Tet1-conjugated nattokinase enzyme for inhibition of Aβ40 plaques in Alzheimer’s disease, Int. J. Nanomedicine. 12 (2017) 8749-8768. https://doi.org/10.2147/IJN.S144545.
Crossref Google Scholar
[68]

H.H. Ahmed, N. Fadl, A.E. Shamy, et al., Miracle enzymes serrapeptase and nattokinase mitigate neuroinflammation and apoptosis associated with Alzheimer’s disease in experimental model, J. Pharm. Pharm. Sci. 3 (2013) 876-891.
Google Scholar
[69]

C. Franceschi, P. Garagnani, P. Parini, et al., Inflammaging: a new immune-metabolic viewpoint for age-related diseases, Nat. Rev. Endocrinol. 14 (2018) 576-590. https://doi.org/10.1038/s41574-018-0059-4.
Crossref Google Scholar
[70]

H. Wu, Y. Wang, Y. Zhang, et al., Breaking the vicious loop between inflammation, oxidative stress and coagulation, a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress, Redox Biol. 32 (2020) 101500. https://doi.org/10.1016/j.redox.2020.101500.
Crossref Google Scholar
[71]

L. Zhou, N. Hao, X. Li, et al., Nattokinase mitigated dextran sulfate sodium-induced chronic colitis by regulating microbiota and suppressing tryptophan metabolism via inhibiting IDO-1, J. Funct. Foods 75 (2020) 104251. https://doi.org/10.1016/j.jff.2020.104251.
Crossref Google Scholar
[72]

Z. Huang, T.K. Ng, W. Chen, et al., Nattokinase attenuates retinal neovascularization via modulation of Nrf2/HO-1 and glial activation, Invest. Ophthalmol. Vis. Sci. 62 (2021) 25. https://doi.org/10.1167/iovs.62.6.25.
Crossref Google Scholar
[73]

M.M.M. Elbakry, S.Z. Mansour, H. Helal, et al., Nattokinase attenuates bisphenol A or gamma irradiation-mediated hepatic and neural toxicity by activation of Nrf2 and suppression of inflammatory mediators in rats, Environ. Sci. Pollut. Res. 29 (2022) 75086-75100. https://doi.org/10.1007/s11356-022-21126-9.
Crossref Google Scholar
[74]

Y. Yan, Y. Wang, J. Qian, et al., Nattokinase crude extract inhibits hepatocellular carcinoma growth in mice, J. Microbiol. Biotechnol. 29 (2019) 1281-1287. https://doi.org/10.4014/jmb.1812.12058.
Crossref Google Scholar
[75]

B. Zhang, J. Chai, L. He, et al., Nattokinase produced by natto fermentation with Bacillus subtilis inhibits breast cancer growth, Int. J. Clin. Exp. Med. 12 (2019) 13380-13387.
Google Scholar
[76]

A.Y.Y. Lee, E.A. Peterson, Treatment of cancer-associated thrombosis, Blood 122 (2013) 2310-2317. https://doi.org/10.1182/blood-2013-04-460162.
Crossref Google Scholar
[77]

M. Huang, Y. Ji, J. Yan, et al., A nano polymer conjugate for dual drugs sequential release and combined treatment of colon cancer and thrombotic complications, Mater. Sci. Eng. C. Mater. Biol. Appl. 110 (2020) 110697. https://doi.org/10.1016/j.msec.2020.110697.
Crossref Google Scholar
[78]

Y. Kou, R. Feng, J. Chen, et al., Development of a nattokinase–polysialic acid complex for advanced tumor treatment, Eur. J. Pharm. Sci. 145 (2020) 105241.
Crossref Google Scholar
[79]

T. Merrill, A. Kanaan, Managing chronic rhinosinusitis with nasal polyps in the elderly: challenges and solutions, Clin. Interv. Aging 17 (2022) 685-698. https://doi.org/10.2147/CIA.S279765.
Crossref Google Scholar
[80]

T. Takabayashi, Y. Imoto, M. Sakashita, et al., Nattokinase, profibrinolytic enzyme, effectively shrinks the nasal polyp tissue and decreases viscosity of mucus, Allergol. Int. 66 (2017) 594-602. https://doi.org/10.1016/j.alit.2017.03.007.
Crossref Google Scholar
[81]

A.K. Palmer, B. Gustafson, J.L. Kirkland, et al., Cellular senescence: at the nexus between ageing and diabetes, Diabetologia. 62 (2019) 1835-1841. https://doi.org/10.1007/s00125-019-4934-x.
Crossref Google Scholar
[82]

H.J. Yang, M.J. Kim, D.Y. Kwon, et al., Combination of aronia, red ginseng, shiitake mushroom and nattokinase potentiated insulin secretion and reduced insulin resistance with improving gut microbiome dysbiosis in insulin deficient type 2 diabetic rats, Nutrients 10 (2018) 948. https://doi.org/10.3390/nu10070948.
Crossref Google Scholar
[83]

S. Park, C.J. Kim, K.C. Ha, et al., Efficacy and safety of aronia, red ginseng, shiitake mushroom, and nattokinase mixture on insulin resistance in prediabetic adults: a randomized, double-blinded, placebo-controlled trial, Foods 10 (2021) 1558. https://doi.org/10.3390/foods10071558.
Crossref Google Scholar
[84]

J.J. Joseph, P. Deedwania, T. Acharya, et al., Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the american heart association, Circulation 145 (2022) e722-e759. https://doi.org/10.1161/CIR.0000000000001040.
Crossref Google Scholar
[85]

N. Wen, S. Lü, X. Xu, et al., A polysaccharide-based micelle-hydrogel synergistic therapy system for diabetes and vascular diabetes complications treatment, Mater. Sci. Eng. C. Mater. Biol. Appl. 100 (2019) 94-103. https://doi.org/10.1016/j.msec.2019.02.081.
Crossref Google Scholar
[86]

X. Li, X. Yang, M. Umar, et al., Expression of a novel dual-functional polypeptide and its pharmacological action research, Life Sci. 267 (2021) 118890. https://doi.org/10.1016/j.lfs.2020.118890.
Crossref Google Scholar
[87]

A. Takano, A. Hirata, K. Ogasawara, et al., Posterior vitreous detachment induced by nattokinase (subtilisin NAT): a novel enzyme for pharmacologic vitreolysis, Invest. Ophthalmol. Vis. Sci. 47 (2006) 2075-2079. https://doi.org/10.1167/iovs.05-0130.
Crossref Google Scholar
[88]

T. Tanikawa, Y. Kiba, J. Yu, et al., Degradative effect of nattokinase on spike protein of SARS-CoV-2, Molecules 27 (2022) 6. https://doi.org/10.3390/molecules27175405.
Crossref Google Scholar
[89]

H. Wu, H. Wang, F. Xu, et al., Acute toxicity and genotoxicity evaluations of Nattokinase, a promising agent for cardiovascular diseases prevention, Regul. Toxicol. Pharmacol. 103 (2019) 205-209. https://doi.org/10.1016/j.yrtph.2019.02.006.
Crossref Google Scholar
[90]

R. Feng, J. Li, J. Chen, et al., Preparation and toxicity evaluation of a novel nattokinase-tauroursodeoxycholate complex, Asian J. Pharm. Sci. 13 (2018) 173-182. https://doi.org/10.1016/j.ajps.2017.11.001.
Crossref Google Scholar
[91]

H. Guo, Y.H. Ban, Y. Cha, et al., Comparative anti-thrombotic activity and haemorrhagic adverse effect of nattokinase and tissue-type plasminogen activator, Food Sci. Biotechnol. 28 (2019) 1535-1542. https://doi.org/10.1007/s10068-019-00580-1.
Crossref Google Scholar
[92]

B.J. Lampe, J.C. English, Toxicological assessment of nattokinase derived from Bacillus subtilis var. natto, Food Chem. Toxicol. 88 (2016) 87-99. https://doi.org/10.1016/j.fct.2015.12.025.
Crossref Google Scholar
[93]

G. Gallelli, G. Di Mizio, C. Palleria, et al., Data recorded in real life support the safety of nattokinase in patients with vascular diseases, Nutrients 13 (2021) 2031. https://doi.org/10.3390/nu13062031.
Crossref Google Scholar
[94]

L. Ramachandran, A. Aqeel, A. Jafri, et al., Nattokinase-associated hemoperitoneum in an elderly woman, Cureus. 13 (2021) e20074. https://doi.org/10.7759/cureus.20074.
Crossref Google Scholar
[95]

K. Awatani-Yoshidome, T. Hashimoto, T. Satoh, Anaphylaxis from nattokinase in a patient with fermented soybean (natto) allergy, Allergol. Int. 71 (2022) 153-154. https://doi.org/10.1016/j.alit.2021.08.004.
Crossref Google Scholar
[96]

F. Zhang, J. Zhang, R.J. Linhardt, Interactions between nattokinase and heparin/GAGs, Glycoconj. J. 32 (2015) 695-702. https://doi.org/10.1007/s10719-015-9620-8
Crossref Google Scholar
[97]

Y.Y. Chang, J.S. Liu, S.L. Lai, et al., Cerebellar hemorrhage provoked by combined use of nattokinase and aspirin in a patient with cerebral microbleeds, Intern. Med. 47 (2008) 467-469. https://doi.org/10.2169/internalmedicine.47.0620.
Crossref Google Scholar
[98]

S. Takagaki, M. Suzuki, E. Suzuki, et al., Unsaturated fatty acids enhance the fibrinolytic activity of subtilisin NAT (nattokinase), J. Food Biochem. 44 (2020) e13326. https://doi.org/10.1111/jfbc.13326.
Crossref Google Scholar
[99]

M. Ero, C. Ng, T. Mihailovski, et al., A pilot study on the serum pharmacokinetics of Nattokinase in humans following a single, oral, daily dose, Altern. Ther. Health Med. 19 (2013) 16-19.
Google Scholar
[100]

M. Fujita, K. Hong, Y. Ito, et al., Transport of nattokinase across the rat intestinal tract, Biol. Pharm. Bull. 18 (1995) 1194-1196. https://doi.org/10.1248/bpb.18.1194.
Crossref Google Scholar
[101]

C. Guan, W. Cui, J. Cheng, et al., Development of an efficient autoinducible expression system by promoter engineering in Bacillus subtilis, Microb. Cell Fact. 15 (2016) 66. https://doi.org/10.1186/s12934-016-0464-0.
Crossref Google Scholar
[102]

Z. Liu, W. Zheng, C. Ge, et al., High-level extracellular production of recombinant nattokinase in Bacillus subtilis WB800 by multiple tandem promoters, BMC Microbiol. 19 (2019) 89. https://doi.org/10.1186/s12866-019-1461-3.
Crossref Google Scholar
[103]

J. Cheng, C. Guan, W. Cui, et al., Enhancement of a high efficient autoinducible expression system in Bacillus subtilis by promoter engineering, Protein Expr. Purif. 127 (2016) 81-87. https://doi.org/10.1016/j.pep.2016.07.008.
Crossref Google Scholar
[104]

J. Xiao, B. Peng, Z. Su, et al., Facilitating protein expression with portable 5’-UTR secondary structures in Bacillus licheniformis, ACS Synth. Biol. 9 (2020) 1051-1058. https://doi.org/10.1021/acssynbio.9b00355.
Crossref Google Scholar
[105]

M. Weng, X. Deng, W. Bao, et al., Improving the activity of the subtilisin nattokinase by site-directed mutagenesis and molecular dynamics simulation, Biochem. Biophys. Res. Commun. 465 (2015) 580-586. https://doi.org/10.1016/j.bbrc.2015.08.063.
Crossref Google Scholar
[106]

Z. Liu, H. Zhao, L. Han, et al., Improvement of the acid resistance, catalytic efficiency, and thermostability of nattokinase by multisite-directed mutagenesis, Biotechnol. Bioeng. 116 (2019) 1833-1843. https://doi.org/10.1002/bit.26983.
Crossref Google Scholar
[107]

Y.M. Vianney, S.E.E. Tjoa, R. Aditama, et al., Designing a less immunogenic nattokinase from Bacillus subtilis subsp. natto: a computational mutagenesis, J. Mol. Model. 25 (2019) 1-12. https://doi.org/10.1007/s00894-019-4225-y.
Crossref Google Scholar
Food Science and Human Wellness
Volume 13 Issue 5,
September 2024
Pages 2401-2409
DOI: 10.26599/FSHW.2022.9250198
Cite this article:
Wu H, Zhang Q, Suo H, et al. Nattokinase as a functional food ingredient: therapeutic applications and mechanisms in age-related diseases. Food Science and Human Wellness, 2024, 13(5): 2401-2409. https://doi.org/10.26599/FSHW.2022.9250198

1618

Views

240

Downloads

1

Crossref

0

Web of Science

0

Scopus

0

CSCD

Altmetrics
Received: 17 November 2022
Revised: 12 January 2023
Accepted: 05 March 2023
Published: 10 October 2024
© 2024 Beijing Academy of Food Sciences. Publishing services by Tsinghua University Press.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Return