Abstract
Fermented soy products, such as cheonggukjang ( japanese natto ), doenjang ( soy sauce paste ), ganjang ( soy sauce ), and douchi, are widely consumed in East asian countries and are major sources of bioactive compounds. The zymosis of cooked soy with bacteria ( Bacillus spp. ) and fungi ( Aspergillus spp. and Rhizopus spp. ) produces a variety of fresh compounds, most of which possess health benefits. This review is focused on the preventive and ameliorating electric potential of ferment soy foods and their components to manage neurodegenerative diseases, including Alzheimer ’ s and Parkinson ’ second diseases. Keywords:
fermented soybean products, Parkinson’s disease, Alzheimer’s disease, isoflavones, gut microbiota
1. Introduction
population aging is a global demographic tendency. According to the “ 2019 Revision of World Population Prospects ” [ 1, 2 ], the proportion of people aged 65 years or over global is projected to reach about 16 % by 2050, and 23 % by 2100. however, this stretch life anticipation is closely associated with a vulnerability to age-related disorders, such as neurodegenerative diseases, including Alzheimer ’ south disease ( AD ) and Parkinson ’ south disease ( PD ) [ 3 ]. unfortunately, there is presently no effective treatment for these annihilating diseases. recently, an increasing number of studies have focused on the development of dietary measures adenine well as preventive regimens for these conditions [ 4, 5 ]. For case, the root of Angelica gigas and Platycodon grandiflorus, ampere well as Lactobacillus helveticus and phosphatidylserine, have been approved regarding the claim of cognition improvement by the korean politics, which allowed them to be processed and marketed as health functional foods. The nutritional values and medicative effects of soy or its constituents are well documented [ 6, 7, 8, 9, 10, 11 ]. In respective asian countries, including China, Indonesia, Japan, and Korea, fermented soy products, such as doenjang ( soy glue and japanese miso ), ganjang ( soy sauce sauce ), natto, and tempeh, have been extensively consumed since ancient times. numerous studies published in the past decades have revealed that fermented soy products have many-sided health benefits, such as serum cholesterol-lowering, anti-diabetic, anti-hypertensive, anti-cardiovascular, and anti-neuroinflammatory effects [ 10, 12, 13, 14 ]. recently, soy and its fermented products have received much attention regarding their effects on the intestine microbiota, which are linked to the pathogenesis of versatile neurological disorders, including depression, anxiety, autism, AD, and PD [ 15, 16, 17 ]. This review article discusses the protective effects of democratic fermented soy sauce foods and their components in the context of neurodegenerative diseases, with a focus on AD and PD, and describes the possible mechanism underlying the beneficial effects of these foods .
2. Types of Fermented Soy Products
soy has been processed into numerous types of products, such as soya milk, bean curd, sprouts, and fermented products ( ). The ferment products of soy include doenjang ( soy spread ), ganjang ( soy sauce ), Korean cheonggukjang, japanese natto, Korean gochujang, indonesian tempeh, sieng ( Cambodia, Laos ), pepok ( Myanmar ), thua nao ( Thailand ), and knema ( India, Nepal, and Bhutan ) [ 18 ] .
Open in a separate window korean cheonggukjang and japanese natto are both produce via two main steps, i.e., cooking and agitation. In the first step, soy is soaked in water at room temperature for 18 h, followed by steaming at 121 °C for 30 min. The second footstep consists in the agitation of fudge soy with airborne Bacillus species, including bacillus subtilis, originating from the ambient environment or from inoculation for 48 h ( ) [ 19 ]. While most of these products, including cheonggukjang and natto, are fermented with Bacillus spp., some products, such as doenjang, soy sauce, and tempeh, are manufactured by fermenting cook soy with fungi, such as Aspergillus and Rhizopus, resulting in the extensive dislocation of soy components and the production of novel bioactive compounds [ 18 ]. Douchi, which is a traditional chinese food that is prepare using fermented and salted black soybeans, has been a popular flavorer in foods and a family medicine in China for centuries [ 20 ]. Sufu or furu is one of the ferment soy products, which has been consumed as a side serve in China over the centuries [ 21, 22 ]. Sufu is a cheese-like merchandise that is made by Aspergillus oryzae in solid-state agitation of salted and ripened tofu through activities of hydrolytic enzymes, such as protease, α-amylase, β-amylase, and lipase [ 21, 22 ] .
4. Isoflavones and Neurodegenerative Diseases
ad and PD, the two most common neurodegenerative disorders, are characterized by a series of events encompassing abnormal protein collection, oxidative stress, neuroinflammation, and neural death. The canonic molecular changes of AD include the formation of insoluble amyloid beta peptide ( Aβ ) aggregates and neurofibrillary tangles ( NFTs ) primed by the hyperphosphorylated tau protein. PD is characterized by the intracellular collection of insoluble α-synuclein and the formation of Lewy bodies in neurons and glial cells [ 85 ]. This abnormal protein deposition contributes to neural dysfunction and degeneration, and foster impairs the architecture and serve of nervous circuits in particular areas of the brain [ 85, 86, 87 ]. As oxidative try and neuroinflammation are widely believed to be critical events in the diseased development of AD and PD, compounds with antioxidative and/or anti-inflammatory activeness are expected to retard the progress of these two neurodegenerative diseases .
4.1. Isoflavones and AD
Soy isoflavones have been reported to have neuroprotective effects in assorted animal studies. In particular, the compounds were shown to attenuate AD-related pathology and reduce its progress. These effects of isoflavones are most likely associated with their antioxidative activity and their affinity for estrogen receptors [ 88 ]. In an experiment using a sneak model, soy sauce isoflavones significantly attenuated galactose-induced oxidative stress, as evidenced by the reversion of the oxidative stress- and AD-related parameters, such as increased serum levels of thiobarbituric-acid-reactive substances in the brain and serum ; increased levels of protein-bound carbonyl in the brain, kidney and liver-colored ; increased serum levels of advanced glycation end products ; and increased expression of caspase-3 and Bax in splenocytes and of Aβ, β-amyloid harbinger protein-cleaving enzyme-1 ( BACE-1 ), and presenilin-1 ( a fractional monetary unit of γ-secretase ) in the brain [ 89 ]. In addition, dietary isoflavones improved cognitive function in an ovariectomized rat model of AD [ 90 ]. Among the isoflavones, genistein was reported to ameliorate the Aβ-induced impairments creditworthy for neural death in AD animal models by exerting antioxidant natural process, abating Aβ toxicity, inhibiting azotic oxide ( NO ) generation, and reducing tau pathology [ 90, 91 ]. Another study besides demonstrated that soy sauce isoflavones reduced neural death and prevent degeneration of the anxious system through anti-inflammatory activity, rule of cellular telephone signaling pathways, and antioxidant action [ 92 ] .
4.2. Isoflavones and PD
Genistein has been reported to protect dopaminergic neurons against lipopolysaccharide ( LPS ) -induced neuroinflammation in a PD model [ 93 ]. furthermore, it suppresses the production of superoxide, tumor necrosis divisor alpha ( TNFα ), and azotic oxide ( NO ) in microglia and mesencephalic neuron–glia cultures [ 88 ]. Microglial cells in the brain are triggered by contagion or injury, thereby releasing proinflammatory mediators, such as cytokines and reactive oxygen species ( ROS ) [ 94, 95 ]. These cytokines and ROS may facilitate the formation of complexes with proteins, therefore altering the officiate of crucial proteins and finally causing cell death [ 95 ]. interestingly, genistein was found to inhibit the accumulation and production of ROS and NO, thus protecting dopaminergic neurons from oxidative neural injury [ 88, 94 ]. In addition, genistein exerted a protective effect on dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( MPTP ) -induced PD mouse, which was likely attributable to the suppression of apoptotic neural cellular telephone death in midbrain via the upregulation of the Bcl 2 gene [ 96 ]. Daidzein was besides reported to attenuate the LPS-induced expression of inflammatory mediators in a murine microglial BV-2 cell occupation. More specifically, pre-exposure of cells to daidzein significantly suppressed the expression of the proinflammatory factors NO and interleukin 6 ( IL-6 ), with moisten of p38 mitogen-activated protein kinase ( MAPK ) phosphorylation, nuclear factor kappa-light-chain-enhancer of activated B cells ( NF-κB ) energizing, and ROS production [ 97 ]. A late report demonstrated that soy isoflavones attenuated the oxidative stress and excitement induced by atrazine, as indicated by malondialdehyde accretion and glutathione depletion, and increased TNFα and IL-6 turn, respectively, in the substantia nigger. In addition, atrazine downregulated LC3-II and Beclin-1 and upregulated p62 in the substantial nigger, suggesting autophagy prohibition. In contrast, these effects were reversed by pre-treatment with soy isoflavones, suggesting that the compounds can restore the autophagy function of dopaminergic neurons in the substantia nigger. In fact, the dysregulation of autophagy is emerging as a major etiology of PD as reported by a number of studies [ 92, 98, 99, 100 ]. In finical, restoring mitochondria-specific autophagy ( term mitophagy ) in PD neurons has been demonstrated to prevent oxidative stress and dopaminergic neural damage in in vivo models and in patient-derived cells [ 98, 101, 102, 103 ]. furthermore, isoflavones ( daidzein, genistein, biochanin A, and formononetin ) induce mitochondrial biosynthesis in myoblasts and nephritic cells through the activation of the NAD-dependent deacetylase sirtuin-1 ( SIRT1 ) /peroxisome proliferator-activated receptor gamma coactivator 1-alpha ( PGC-1α ) pathway [ 104, 105 ]. In turn, genistein upregulates the estrogen-related receptor alpha ( ERR-α ), ERR-β, PGC-1α, SIRT3, and the nuclear factor erythroid 2-related agent 2 ( Nrf2 ) downstream enzyme, thus enhancing mitochondrial biosynthesis and antioxidant responses [ 106 ]. Considering the effects of isoflavones on mitochondrial biogenesis and mitophagy in several tissues, it is highly plausible that isoflavones regulate mitochondrial homeostasis in the central aflutter organization ( CNS ) [ 107, 108 ]. As respective studies reported that PD is associated with dysregulated mitophagy, isoflavones in soy sauce products offer a good curative and/or preventive electric potential for PD [ 92, 98, 99, 100 ] .
5. Other Components in Fermented Soy Products and Neurodegenerative Diseases
As mentioned previously, it is most likely that antioxidants have a beneficial effect on neurodegenerative diseases, which are well related to oxidative stress. Fermented soy products have been reported to contain not only isoflavones, but besides early antioxidant molecules .
5.1. Amino Acids and Peptides with Antioxidant Activity
holocene studies reported that the spare amino acids, such as alanine, glycine, histidine, leucine, methionine, phenylalanine, tryptophan, tyrosine, and valine, stage in peptides have antioxidant action [ 109, 110, 111 ]. For example, the radical scavenge activities of a peptide can be attributed to imidazole, indole, and phenol groups in histidine, tryptophan, and tyrosine, respectively [ 110, 112 ], in which those chemical groups can easily donate protons to electron-deficient radicals [ 111 ]. Watanabe and coworkers besides claimed that the amino acids and peptides formed during agitation are responsible for antioxidant activity in the water-soluble fraction of Rhizopus-fermented tempeh [ 38 ] ; the contents of free amino acids and peptides were found to increase during the aerobic agitation with Rhizopus, with attendant increase in antioxidant natural process in the water-soluble fraction .
5.2. Soyasaponins
Soyasaponins have been reported to significantly inhibit NF-κB energizing in LPS-treated microglial BV-2 cells. In particular, soyasapogenol B ( SB ) recovered LPS-induced cognitive deficit in a shiner model [ 113 ]. Furthermore, SB significantly increased camp response element-binding protein phosphorylation and brain-derived neurotrophic factor formula in LPS-treated mouse and corticosterone-stimulated SH-SY5Y cells, and inhibited NF-κB activation in LPS-treated mouse. Soyasaponin subclasses A1, A2, and I besides inhibited the LPS-induced cyclooxygenase 2 ( COX-2 ) formulation in a dose-dependent manner through negative regulation of NF-kB. These studies systematically suggest that soyasaponins attenuate memory deficits by suppressing NF-κB-mediated inflammation [ 113, 114 ] .
6. Effect of Fermented Soy Products and Gut Microbiota on Neurodegenerative Diseases
It is well established that even the short-run dietary intake intake of fermented soy products can affect the typography of the human gut microbiota. For case, an animal-based diet decreases the levels of Firmicutes, which metabolize dietary implant polysaccharides ( Eubacterium rectale, Roseburia, and Ruminococcus bromii ), while increasing the abundance of bile-tolerant microorganisms ( Alistipes, Bacteroides, and Bilophila ) [ 115, 116 ]. A large-scale genome-wide analysis of human faecal samples demonstrated that the consumption of LAB-containing foods is reflected in the gut microbial balance [ 117 ] .
6.1. Fermented Soy Products and Gut Microbiota
The zymosis of soy confers alone centripetal assign, extends ledge life, modifies the nutritional quality and phytochemical profile, and enhances digestibility. In addition, the microorganisms used in agitation themselves are a good beginning of prebiotics adenine well as probiotics. several holocene studies have reported that the composing and structure of the catgut microbiota could be changed by the pulmonary tuberculosis of fermented soy foods, such as ferment soya milk ( yogurt ), fermented bean curd, soy paste ( doenjang ), and soy sauce ( ganjang ).
Fermented soya milk manufactured using Lactobacillus and Bifidobacterium affects populations of human faecal microbiota [ 118 ] in a desirable way, inducing effects that include relief of menopausal symptoms [ 119 ], control of hypercholesterolemia [ 120 ], modulation of mitogen-stimulated splenocyte proliferation, and TNFα production [ 121 ]. Fermented soy foods prepared with Enterococci and Lactobacilli were shown to increase these bacterial population in the intestine. similarly, water-soluble extracts of soy fermented with Lactobacillus helveticus and Enterococcus faecium were reported to significantly increase the populations of Enterococci, Lactobacilli, and Bifidobacteria in the catgut, and decrease the level of Enterobacteriaceae. The consumption of soya milk fermented by Enterococcus faecium or Lactobacillus plantarum significantly increased the populations of Bifidobacterium, Enterococcus, and Lactobacillus in the gut, while their effect on the abundance of gut Clostridium and Bacteroides was inconsistent. Tempeh, an indonesian traditional fermented soy product, has been shown to increase the proportional abundance of Bifidobacterium, Lactobacillus, Escherichia coli, and Enterococcus in an in vitro gut simulator model. In contrast, the consumption of natto was shown to increase the abundance of Bacillus and Bifidobacterium and decrease Clostridia and Enterobacteriaceae in the intestine microbiota [ 122 ]. Fermented soy products manufactured by traditional methods in Korea are reported to contain high levels of Bacillus species, such as bacillus amyloliquefaciens, Bacillus subtilis, and Bacillus licheniformis [ 123 ]. Nam and coworkers analyzed over 12,000 bacterial pyrosequences in a commercial brand of cheonggukjang and found that the huge majority of bacteria were assigned to the phylum Firmicutes ( > 95 % ), followed by Proteobacteria ( < 5 % ). Most of the Firmicutes were Bacillus species, although the levels of bacillus subtilis ( 1.1–45.2 % ), Bacillus licheniformis ( 3.2–33.6 % ), and Bacillus amyloliquefaciens ( 0.2–9.2 % ) varied greatly according to mark. In some cheonggukjang samples, particular unclassified Bacillus species and lactic acid bacteria were the dominant microbes [ 124 ]. Kim and coworkers examined the bacterial communities in meju and besides found that the prevailing phylum was Firmicutes ( 93.6 % ) [ 125 ]. late studies demonstrated that the pulmonary tuberculosis of cheonggukjang fermented by bacillus subtilis or Bacillus amyloliquefaciens increased the abundance of Bifidobacteriales and Lactobacillales in the catgut. however, the population of Enterobacteriales, which are considered harmful bacteria, were lowered by a cheonggukjang-containing diet [ 126, 127 ] .
6.2. Gut Microbiota and Neurodegenerative Diseases
Emerging testify powerfully supports the notion that gut microbial writing and balance is closely associated with the risk of neurodegenerative diseases. The human gastrointestinal ( GI ) tract is estimated to harbor 100 trillion microorganisms, generally called the intestine microbiota, which is determined by both host genetics and environmental factors [ 128, 129 ]. An increasing total of studies have shown that the gut microbiota critically affects the function and development of the CNS [ 15 ] .
6.2.1. Gut Microbiota and PD
PD is a multifactorial neurodegenerative disease that is believed to be caused by both genetic changes and environmental factors. It is characterized by the deposition of toxic α-synuclein inclusions that lead to the death of dopaminergic neurons in the corpus striatum and, consequently, motor dysfunction [ 130, 131 ]. The pathogenesis of PD has been speculated to be associated with the GI tract as α-synuclein deposit was observed in the peripheral aflutter system, specially in the enteric and pelvic plexus, of patients with PD [ 132 ]. A subsequent study suggested that the PD pathology originates from the peripheral organs in which α-synuclein is seeded, such as the GI tract and adenoidal cavity, before being retrograde transported to the cerebral cerebral cortex through the vagal nerve [ 132, 133 ]. Furthermore, many patients with PD experience hyposmia and GI problems anterior to the materialization of authoritative PD symptoms, and patients with incendiary intestine disease are besides at a higher risk of developing PD [ 134 ]. Thus, the microbiota present in the GI tract are most likely involved in the pathogenesis of PD, in a direct or indirect manner. The apoptotic death of dopaminergic neural cells in the substantia nigger has been widely believed to be triggered by oxidative stress [ 135, 136 ]. excessive production of ROS can cause oxidative damage in the mind of patients with PD, as shown by increase DNA damage and lipid peroxidation in the substantia nigger [ 18 ]. Increase in protein oxidation is besides observed in many areas of the brain, with the substantia nigger being particularly susceptible [ 137, 138 ]. therefore, it is expected that antioxidants will attenuate and/or prevent the progress of PD. As mentioned above, naturally occurring antioxidants have a dear potential to attenuate and/or prevent the progress of PD, which is associated with neural apoptosis triggered by excessive ROS production and a diminished capability to handle oxidative stress by dopaminergic neurons and/or neighboring tissues. The zymosis of soy produces several antioxidative compounds, such as peptides, aglycone forms of isoflavones, and soyasaponins ; therefore, it is most probably that fermented soy products alleviate the progress and aggravation of PD. Soy protein, which normally represents approximately 40 % of the seed contented, is degraded into peptides by microbial proteases during agitation. The peptides produced from soy sauce proteins exhibit diverse beneficial effects, including antioxidant natural process, which regulate the oxidation-reduction balance in the catgut and subsequently influence the gut microbiota in a positive manner [ 139, 140 ]. Gut microbiota have been reported to preferentially zymosis peptides over free amino acids [ 141 ], and some peptides possess high resistance against gastrointestinal digestion [ 142 ] ; therefore, these peptides can affect the composition of intestine microbiota and can be utilized by the intestine microbiota to produce neurotransmitters, such as butyrate [ 141 ], which may improve the negative symptoms of neurodegenerative diseases [ 143 ]. In fact, butyrate greatly regulates immune functions and department of energy metabolism of hosts, and mediates host–microbe crosstalk through transporters ( MCT1/SLC16A1 ; SMCT1/SLC5A8 ) and specific receptors ( GPR43/FFAR2 ; GPR41/FFAR3 ; GPR109a/HCAR2 ). The effect of butyrate may besides be mediated by the β-oxidation nerve pathway and the inhibition of histone deacetylases ( HDACs ), leading to enhanced histone acetylation and gene expression in master of ceremonies cells. Butyrate is besides widely used as an experimental pharmacological compound and, more recently, in neuroscience research [ 144, 145 ]. frankincense, this compound has been in the spotlight in research into the microbiota–gut–brain axis, to understand how gut-derived butyrate affects mind functions and behaviors, ranging from depression to neurodegenerative diseases and cognitive damage [ 146 ]. late studies have demonstrated that a probiotic assortment of Lactobacillus rhamnosus GG, Bifidobacterium animalis lactis, and Lactobacillus acidophilus increases butyrate and subsequently rescues the nigral dopaminergic neurons from MPTP-and rotenone-induced neurotoxicity in a mouse model [ 147 ]. The neuroprotective effect of butyrate may be mediated by the upregulation of occludins, zonule occludens-1, and Bcl-2, and, in particular, the stimulation of the colonic glucagon-like peptide-1 ( GLP-1 ) and the upregulation of brain GLP-1R [ 51 ] .
6.2.2. Gut Microbiota and AD
Disturbances in the composition of intestine microbiota are related to immune activation and increase permeability of the gut barrier, therefore leading to systemic ignition, which, in turning, may compromise the blood–brain barrier and gun trigger neuroinflammation, neural damage, and neurodegeneration. More specifically, age-related alterations in the gut microbiota characterized by lower diverseness and constancy may lead to an ceaseless inflammatory department of state of the gut mucous membrane, ultimately resulting in chronic systemic inflammation, including neuroinflammation [ 148, 149, 150 ]. It has been reported that the gut microbial composition of patients with AD is hallmarked by a decreased abundance of Firmicutes and Actinobacteria, and an increased abundance of Bacteroidetes and Proteobacteria. More specifically, the families that were reduced within the Firmicutes phylum include Clostridiaceae, Mogibacteriaceae, Peptostreptococcaceae, Ruminococcaceae, and Turicibacteraceae. The Acinetobacteria and Bifidobacteriaceae families were reduced in the gut of patients with AD. In contrast, Bacteroidaceae and Rikenellaceae within the Bacteroidetes phylum were increased in these individuals. In general, patients with AD harbor an increase number of proinflammatory bacteria, such as Bacteroidetes and Proteobacteria ( Escherichia and Shigella ), and have decreased anti-inflammatory bacteria ( Firmicutes, Bifidobacterium, and Eubacterium rectale ). however, extra research is required to establish a solid correlation between gut microbiota and AD, as the alterations in the gut microbiota of patients with AD were not coherent among studies [ 151 ]. A plant-based good foods diet containing probiotics, soybeans, nuts, omega-3 fatty acid polyunsaturated fatty acids, and antioxidants, angstrom well as a first gear intake of impregnate fats, animal-derived foods, and refined sugar, has been reported to inhibit the inflammatory reception, rarefy insulin resistance, and lower the risk of cognitive disability and AD [ 152, 153 ]. The intake of cheonggukjang fermented with Bacillus species prevents and alleviates the memory stultification observed in patients with AD and cerebral ischemic condition. In particular, cheonggukjang, which contains a high poly-L-γ-glutamic acid ( γ-PGA ), exhibited better efficacy for improving glucose metamorphosis and neural cell survival than did a moo level of γ-PGA [ 126 ], although the neuroprotective effect and related mechanism ( s ) of γ-PGA stay ill-defined. Yang and colleagues reported that soybeans fermented with Bacillus licheniformis enhanced cognitive routine in diabetic rats with AD-type dementia [ 154 ]. several proteinases produced by Bacillus pumilus and Bacillus subtilis and present in ferment soy products posse amyloid-degrading activeness ; consequently, they can be developed into anti-aggregation drugs [ 155, 156 ], although many hurdles in the delivery of the proteases to target sites are anticipated. Another learn found that bacillus subtilis, a microorganism that is prevailing in traditionally made cheonggukjang, restored the life of Caenorhabditis elegans strains that expressing Aβ to values exchangeable to the life anticipation of the wild-type tune [ 157 ]. The direct effects of microorganism in AD models are believed to be associated with the ability of bacillus subtilis to biosynthesize quorum-sensing peptides ( i, the competence and monogenesis factor ) and form a gut-associated biofilm, which is associated with the anti-aging consequence .
7. Conclusions
The collection of toxic unique proteins or peptides characterized by abnormal conformational properties inside neural cells in the genius is a common feature of AD and PD, which are the two most prevailing neurodegenerative diseases with an incidence that keeps increasing globally. These peptides or proteins normally exert deleterious effects on the CNS through the coevals of ROS, exacerbation of inflammation, alteration of mitochondrial homeostasis, and their combinations. Fermented soy products have long-familiar beneficial effects on neurodegenerative diseases and afford a variety of health benefits, such as the prevention of several chronic diseases. In detail, the release isoflavones generated during the agitation of cook soy may attenuate the progression of AD and PD via antioxidant activeness and the restoration of ROS-mediated mitochondrial dysfunction, as illustrated in .
Open in a separate window holocene studies besides suggested that the regulation of the gut microbiome by fermented soy sauce products can modulate neurodegenerative diseases through metabolites produced by microbial agitation, such as butyrate, or by changing the gut microbial musical composition in a beneficial fashion. however, clinical data regarding the remedy or preventive effects of ferment soy products in neurodegenerative diseases are limited. Further research using large, long-run clinical trials to evaluate fermented soy products and their components would be helpful in making specific dietary recommendations to patients with AD and PD .
Author Contributions
conceptualization, J.-S.K. and C.H.J. ; writing—original draft preparation, J.-S.K. and J.O. and C.H.J. ; writing—review and editing, J.S.L. and H.J.K. ; visual image, J.O. and C.H.J. ; supervision, J.-S.K. All authors have read and agreed to the published version of the manuscript .
Funding
This inquiry was funded by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries ( IPET ) through the Agri-Bio industry Technology Development Program, funded by the Ministry of Agriculture, Food and Rural Affairs ( MAFRA ), Republic of Korea ( Grant No. 319103042HD020 ).
Conflicts of Interest
The authors declare no conflict of interest .
Footnotes
Publisher’s Note: MDPI stays inert with attentiveness to jurisdictional claims in published maps and institutional affiliations .
