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Fermenting seaweed with koji fungi transforms its chemical composition, generating bioactive compounds absent in the raw material. We previously reported that the fungal fermentation of the edible red alga Pyropia yezoensis (Nori) produces betaine structural analogs (such as betaine, stachydrine, and carnitine), which are of particular interest because of their physiological roles and potential health benefits. Using metabolomic profiling, we compared non-fermented Nori with powders fermented by three industrially important fungi: Aspergillus luchuensis mut. kawachii (white koji fungus), Aspergillus oryzae (yellow koji fungus), and Monascus purpureus (red koji fungus). All fermentations enhanced the levels of betaine and carnitine, but stachydrine production was unique to the yellow koji fungus. Precursor patterns revealed distinct metabolic strategies: the yellow koji fungus exhibited an intermediate detectable choline oxidation route and strong proline methylation, the white koji fungus rapidly converted choline without intermediate accumulation, and the red koji fungus favored carnitine and proline but produced little stachydrine. Fermentation also shifted the methylation balance toward a state that supports methyl-dependent pathways. These findings reveal clear species-specific strategies for the production of betaine structural analogs, providing a mechanistic basis for understanding the metabolic divergence among koji fungi and guiding the targeted design of functional seaweed products.

Perilla frutescens (L.) Britton var. frutescens (egoma in Japan) is a traditional oilseed that has several varieties with different photoperiod responses. Although egoma pomace, industrial waste produced during oil extraction, is a rich source of macro- and micro-nutrients such as protein, fiber, minerals, and polyphenols, it has not yet been used for purposes other than livestock feeding. To find out a better use of perilla pomace and its function, we selected four varieties of egoma originating from different regions with different photoperiod responses: two varieties were from Japan, which are broadly cultivated for oilseed and are highly sensitive to light and temperature. The other two varieties from Nepal, which are tolerant to low light and low temperature. Rosmarinic acid-3- O -glucoside, rosmarinic acid, and apigenin-7- O -glucoside were detected as the main polyphenolic constituents in every variety, while apigenin and luteolin were present only in perilla pomace from Japan. In IgE-sensitized RBL-2H3 cells, polyphenols derived from two varieties of Japan suppressed degranulation of mast cells, but those derived from the two varieties of Nepal did not, indicating that apigenin and luteolin may be in part responsible for the anti-allergic response. In addition, it was found that proteins involved in the degranulation signaling pathway, such as PLCγ2, Syk, and Akt, were less phosphorylated in cells treated with the egoma pomace extracts of Japanese origin. Taken together, pomace from egoma varieties derived from different regions may differently modulate allergic response in part due to the difference in polyphenol composition and may be applied to develop nutraceuticals and functional foods fortified with anti-allergic properties.

Lotus root is a traditional food ingredient used primarily in Asia and is rich in polyphenols. To determine its potential use in antiphotoaging, polyphenols were extracted from lotus root with 50% ethanol, and the activity of matrix metalloproteinase (MMP) was measured in dermal cells treated with ultraviolet A (UVA). UVA exposure increased the gene expression of IL-1α, the mRNA levels of MMP-1, and hence, the levels of MMP-1 protein in HaCaT cells, whereas cells treated with lotus polyphenol (LP) normalized these values to the control. In the presence of LP at concentrations of 1 and 10 μg/mL, both the secretion of IL-1α and protein levels of MMP-1 in human keratinocyte cells significantly reduced. Similarly, in the LabCyte EPI-MODEL24, irradiation with UVA caused an increase in mRNA expression of IL-1α and MMP-1, which was prevented by adding LP to the cells. Our results with three different skin cells accordingly showed that LP may help maintain skin health through decreased levels of MMP-1 activity via its anti-inflammatory properties.

Hepatic steatosis is an early stage in the progression of non-alcoholic fatty liver disease (NAFLD) and can lead to the development of non-alcoholic steatohepatitis (NASH), a major cause of liver-related morbidity and mortality. Identification of dietary components that can alleviate hepatic steatosis is crucial for developing effective therapeutic strategies for NAFLD. Recently, we demonstrated the impact of lipids extracted from the marine red alga Susabinori ( Pyropia yezoensis ) in a murine model of type 2-diabete ( db / db ). We found that Susabinori lipids (SNL), abundant in eicosapentaenoic acid (EPA)-containing polar lipids, protected against obesity-induced hepatic steatosis in db / db mice. To understand the specific genes or biological pathways underlying the effects of SNL, we conducted RNA-Seq analysis of the hepatic transcriptome. By performing comparative analysis of differentially expressed genes between normal mice and db / db mice consuming a control diet, as well as SNL-fed db / db mice, we identified the 15 SNL-dependent up-regulated genes that were down-regulated in db / db mice but up-regulated by SNL feeding. Gene ontology and pathway analysis on these 15 genes demonstrated a significant association with the metabolisms of arachidonic acid (AA) and linoleic acid (LA). Furthermore, we observed alterations in the expression levels of monoacylglycerol lipase ( Magl ) and fatty acid-binding protein 4 ( Fabp4 ) in the SNL-fed db / db mice, both of which are implicated in AA and LA metabolism. Additionally, the livers of SNL-fed db / db mice exhibited reduced levels of AA and LA, but a high accumulation of EPA. In conclusion, the SNL diet might affect the metabolisms of AA and LA, which contribute to the improvement of hepatic steatosis. Our findings provide insights into the molecular mechanisms underlying the beneficial effects of SNL.

Edible algae Neopyropia yezoensis is used as “Nori”, its dried sheet product, in Japanese cuisine. Its lipid components reportedly improve hepatic steatosis in obese db/db mice. In this study, we prepared “Nori powder (NP)” and “fermented Nori powder (FNP)” to utilize the functional lipids contained in “Nori” and examined their nutraceutical effects in vivo. Male db/db mice were fed a basal AIN-76 diet, a 10% NP-supplemented diet, or a 10% FNP-supplemented diet for 4 weeks. We detected eicosapentaenoic acid (EPA) present in both NP and FNP in the serum and liver of db/db mice in a dose-dependent manner. The NP diet reduced hepatic triglyceride accumulation (by 58%) in db/db mice by modulating gene expression, which resulted in the inhibition of lipogenic enzyme activity. Additionally, NP intake significantly suppressed the expression of inflammatory genes in the liver and hepatic injury marker levels in the sera (by 26%) of db/db mice. The FNP diet also led to a marked reduction in hepatic triglyceride accumulation (by 50%) and hepatic injury (by 28%) in db/db mice, and the mechanism of these alleviative actions was similar to that of the NP diet. Although the EPA content of FNP was one-third that of NP, metabolomic analysis revealed that bioactive betaine analogs, such as stachydrine, betaine, and carnitine, were detected only in FNP. In conclusion, we suggest that (1) mechanical processing of “Nori” makes its lipid components readily absorbable by the body to exert their lipid-lowering effects, and (2) fermentation of “Nori” produces anti-inflammatory molecules and lipid-lowering molecules, which together with the lipid components, can exert hepatic steatosis-alleviating effects.

Background Nonalcoholic fatty liver disease (NAFLD) is emerging as the most common liver disease of industrialized countries. Thus, discovering food components that can ameliorate NAFLD is of interest. Lotus root, the edible rhizome of Nelumbo nucifera , contains high levels of polyphenolic compounds, and several health-promoting properties of lotus root have been reported. In this study, we tested whether feeding a polyphenolic extract of lotus root to db/db mice protects them from hepatic steatosis. Results After 3 weeks of feeding, the hepatomegaly and hepatic triglyceride accumulation were markedly alleviated in the lotus polyphenol-diet-fed db/db mice relative to the control mice. Although the lipolytic enzyme activity was not changed, the activities of lipogenic enzymes, such as fatty acid synthase and malic enzyme, were significantly lower in the lotus polyphenol diet-fed db/db mice. Additionally, the ESI-IT/MS and MALDI-TOF MS spectra revealed the presence of B-type proanthocyanidin polymers with polymerization degree up to 9 in the polyphenolic lotus root extract. Conclusion We speculate that the condensed tannins contained in lotus root can alleviate hepatic steatosis by suppressing the lipogenic enzyme activity in the livers of db/db mice.

Betaine structural analogs are compounds characterized by the presence of positive and negative charges in a single molecule and have been reported to have physiological properties, such as anti-inflammatory activities. In this study, we performed a metabolomic analysis of metabolite composition changes during the fermentation of Neopyropia yezoensis, an edible red alga, with Aspergillus oryzae for 72 h. The results indicated that three specific betaine structural analogs (betaine, stachydrine, and carnitine) exhibited significant changes in production by the end of the 72 h fermentation period. Time-course analysis suggested that betaine was generated from the precursor choline at 12–24 h during the late stage of fungal growth, while stachydrine was generated from the precursor-related compound glutamic acid at 48–72 h during the sporulation stage. However, the contribution of the precursor lysine to the increased production of carnitine during the 12–72 h period was unclear. This study provides useful information on the efficient production of betaine structural analogs by the fungal fermentation of seaweed as well as various other food materials.

The complex inhibitory effects of inhibitors present in lignocellulose hydrolysate suppress the ethanol fermentation of Saccharomyces cerevisiae. Although the interactive inhibitory effects play important roles in the actual hydrolysate, few studies have investigated glycolaldehyde, the key inhibitor of hot-compressed water-treated lignocellulose hydrolysate. Given this challenge, we investigated the interactive effects of mixed fermentation inhibitors, including glycolaldehyde. First, we confirmed that glycolaldehyde was the most potent inhibitor in the hydrolysate and exerted interactive inhibitory effects in combination with major inhibitors. Next, through genome-wide analysis and megavariate data modeling, we identified SUMOylation as a novel potential mechanism to overcome the combinational inhibitory effects of fermentation inhibitors. Indeed, overall SUMOylation was increased and Pgk1, which produces an ATP molecule in glycolysis by substrate-level phosphorylation, was SUMOylated and degraded in response to glycolaldehyde. Augmenting the SUMO-dependent ubiquitin system in the ADH1-expressing strain significantly shortened the lag phase of growth, released cells from G₂/M arrest, and improved energy status and glucose uptake in the inhibitor-containing medium. In summary, our study was the first to establish SUMOylation as a novel platform for regulating the lag phase caused by complex fermentation inhibitors.

Hepatic steatosis is an early stage in the progression of non-alcoholic fatty liver disease (NAFLD) and can lead to the development of non-alcoholic steatohepatitis (NASH), a major cause of liver-related morbidity and mortality. Identification of dietary components that can alleviate hepatic steatosis is crucial for developing effective therapeutic strategies for NAFLD. Recently, we demonstrated the impact of lipids extracted from the marine red alga Susabinori (Pyropia yezoensis) in a murine model of type 2-diabete (db/db). We found that Susabinori lipids (SNL), abundant in eicosapentaenoic acid (EPA)-containing polar lipids, protected against obesity-induced hepatic steatosis in db/db mice. To understand the specific genes or biological pathways underlying the effects of SNL, we conducted RNA-Seq analysis of the hepatic transcriptome. By performing comparative analysis of differentially expressed genes between normal mice and db/db mice consuming a control diet, as well as SNL-fed db/db mice, we identified the 15 SNL-dependent up-regulated genes that were down-regulated in db/db mice but up-regulated by SNL feeding. Gene ontology and pathway analysis on these 15 genes demonstrated a significant association with the metabolisms of arachidonic acid (AA) and linoleic acid (LA). Furthermore, we observed alterations in the expression levels of monoacylglycerol lipase (Magl) and fatty acid-binding protein 4 (Fabp4) in the SNL-fed db/db mice, both of which are implicated in AA and LA metabolism. Additionally, the livers of SNL-fed db/db mice exhibited reduced levels of AA and LA, but a high accumulation of EPA. In conclusion, the SNL diet might affect the metabolisms of AA and LA, which contribute to the improvement of hepatic steatosis. Our findings provide insights into the molecular mechanisms underlying the beneficial effects of SNL.

Hepatic steatosis is an early stage in the progression of non-alcoholic fatty liver disease (NAFLD) and can lead to the development of non-alcoholic steatohepatitis (NASH), a major cause of liver-related morbidity and mortality. Identification of dietary components that can alleviate hepatic steatosis is crucial for developing effective therapeutic strategies for NAFLD. Recently, we demonstrated the impact of lipids extracted from the marine red alga Susabinori (Pyropia yezoensis) in a murine model of type 2-diabete (db/db). We found that Susabinori lipids (SNL), abundant in eicosapentaenoic acid (EPA)-containing polar lipids, protected against obesity-induced hepatic steatosis in db/db mice. To understand the specific genes or biological pathways underlying the effects of SNL, we conducted RNA-Seq analysis of the hepatic transcriptome. By performing comparative analysis of differentially expressed genes between normal mice and db/db mice consuming a control diet, as well as SNL-fed db/db mice, we identified the 15 SNL-dependent up-regulated genes that were down-regulated in db/db mice but up-regulated by SNL feeding. Gene ontology and pathway analysis on these 15 genes demonstrated a significant association with the metabolisms of arachidonic acid (AA) and linoleic acid (LA). Furthermore, we observed alterations in the expression levels of monoacylglycerol lipase (Magl) and fatty acid-binding protein 4 (Fabp4) in the SNL-fed db/db mice, both of which are implicated in AA and LA metabolism. Additionally, the livers of SNL-fed db/db mice exhibited reduced levels of AA and LA, but a high accumulation of EPA. In conclusion, the SNL diet might affect the metabolisms of AA and LA, which contribute to the improvement of hepatic steatosis. Our findings provide insights into the molecular mechanisms underlying the beneficial effects of SNL.