Antibacterial and Immunosuppressive Effects of a Novel Marine Brown Alga-Derived Ester in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic skin condition that is characterized by dysregulated immune responses and a heightened risk of Staphylococcus aureus infections, necessitating the advancement of innovative therapeutic methods. This study explored the potential of (6Z,9Z,12Z,15Z)-(2R,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl octadeca-6,9,12,15-tetraenoate (HSN-S1), a compound derived from the marine alga Hizikia fusiformis, which shows anti-inflammatory, antimicrobial, and immunomodulatory properties. HSN-S1 was isolated and characterized using advanced chromatographic and spectroscopic methods. Its efficacy was evaluated via in vitro assays with keratinocytes, macrophages, and T cells to assess cytokine suppression and its immunomodulatory effects; its antibacterial activity against S. aureus was quantified. The in vivo effectiveness was validated using a 2,4-dinitrochlorobenzene-induced AD mouse model that focused on skin pathology and cytokine modulation. HSN-S1 significantly reduced pro-inflammatory cytokine secretion, altered T-helper cell cytokine profiles, and showed strong antibacterial activity against S. aureus. In vivo, HSN-S1 alleviated AD-like symptoms in mice and reduced skin inflammation, transepidermal water loss, serum immunoglobulin-E levels, and Th2/Th17 cytokine outputs. These findings suggest HSN-S1 to be a promising marine-derived candidate for AD treatment, as it offers a dual-target approach that could overcome the limitations of existing therapies, hence warranting further clinical investigation.

Experimental and Computational Study to Reveal the Potential of Non-Polar Constituents from Hizikia fusiformis as Dual Protein Tyrosine Phosphatase 1B and α-Glucosidase Inhibitors.

Hizikia fusiformis (Harvey) Okamura is an edible marine alga that has been widely used in Korea, China, and Japan as a rich source of dietary fiber and essential minerals. In our previous study, we observed that the methanol extract of H. fusiformis and its non-polar fractions showed potent protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibition. Therefore, the aim of the present study was to identify the active ingredient in the methanol extract of H. fusiformis. We isolated a new glycerol fatty acid (13) and 20 known compounds including 9 fatty acids (1-3, 7-12), mixture of 24R and 24S-saringosterol (4), fucosterol (5), mixture of 24R,28R and 24S,28R-epoxy-24-ethylcholesterol (6), cedrusin (14), 1-(4-hydroxy-3-methoxyphenyl)-2-[2-hydroxy -4-(3-hydroxypropyl)phenoxy]-1,3-propanediol (15), benzyl alcohol alloside (16), madhusic acid A (17), glycyrrhizin (18), glycyrrhizin-6'-methyl ester (19), apo-9'-fucoxanthinone (20) and tyramine (21) from the non-polar fraction of H. fusiformis. New glycerol fatty acid 13 was identified as 2-(7'- (2″-hydroxy-3″-((5Z,8Z,11Z)-icosatrienoyloxy)propoxy)-7'-oxoheptanoyl)oxymethylpropenoic acid by spectroscopic analysis using NMR, IR, and HR-ESI-MS. We investigated the effect of the 21 isolated compounds and metabolites (22 and 23) of 18 against the inhibition of PTP1B and α-glucosidase enzymes. All fatty acids showed potent PTP1B inhibition at low concentrations. In particular, new compound 13 and fucosterol epoxide (6) showed noncompetitive inhibitory activity against PTP1B. Metabolites of glycyrrhizin, 22 and 23, exhibited competitive inhibition against PTP1B. These findings suggest that H. fusiformis, a widely consumed seafood, may be effective as a dietary supplement for the management of diabetes through the inhibition of PTP1B.

Dietary Hizikia fusiformis glycoprotein-induced IGF-I and IGFBP-3 associated to somatic growth, polyunsaturated fatty acid metabolism, and immunity in juvenile olive flounder Paralichthys olivaceus.

This study was aimed to examine the effect of dietary glycoprotein extracted from the sea mustard Hizikia fusiformis (Phaeophyceae: Sargassaceae) as a dietary supplement on growth performance in association with somatotropin level, proximate compositions, and immunity in juvenile olive flounder Paralichthys olivaceus. Water-ethanol extracted glycoprotein from H. fusiformis was supplemented to three fishmeal-based diets at the concentration of 0, 5, and 10gkg(-1) diet (designated as H0, H5, and H10, respectively). After a 12week-long feeding trial, growth performance and biochemical responses were analyzed including proximate composition, and whole body amino acids and fatty acids. We also measured plasma insulin like growth factor (IGF), IGF-binding protein (IGFBP) and interleukin (IL). The fish fed H5 showed the greatest weight gain among the dietary treatments. In parallel with the growth, the fish fed the diets containing H. fusiformis glycoprotein showed an increased plasma IGF-I activity and increased expression of 43-kDa IGFBP-3 compared to that in the control, whereas an opposite trend was observed for 34-kDa IGFBP-1. Although no differences were found in the level of whole body linoleic acid (C18:2n-6) and linolenic acid (C18:3n-3) among treatments, increases in arachidonic acid (ARA, C20:4n-6), eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) were observed in fish fed H5 compared to control. IL-2 and -6 levels increased significantly in fish fed H10 compared to those in the control indicating increased immunity. These results suggest that supplementation of H. fusiformis glycoprotein in fish diet may be beneficial for fish growth and immunity in juvenile olive flounder.

Hizikia fusiformis: Pharmacological and Nutritional Properties.

The brown seaweed Hizikia fusiformis (syn. Sargassum fusiforme), commonly known as "Hijiki", has been utilized in traditional cuisine and medicine in East Asian countries for several centuries. H. fusiformis has attracted much attention owing to its rich nutritional and pharmacological properties. However, there has been no comprehensive review of the nutritional and pharmacological properties of H. fusiformis. The aim of this systematic review was to provide detailed information from the published literature on the nutritional and pharmacological properties of H. fusiformis. A comprehensive online search of the literature was conducted by accessing databases, such as PubMed, SpringerLink, ScienceDirect, and Google Scholar, for published studies on the nutritional and pharmacological properties of H. fusiformis between 2010 and 2021. A total of 916 articles were screened from all the databases using the preferred reporting items for systematic reviews and meta-analyses method. Screening based on the setdown criteria resulted in 59 articles, which were used for this review. In this review, we found that there has been an increase in the number of publications on the pharmacological and nutritional properties of H. fusiformis over the last 10 years. In the last 10 years, studies have focused on the proximate, mineral, polysaccharide, and bioactive compound composition, and pharmacological properties, such as antioxidant, anticancer, antitumor, anti-inflammatory, photoprotective, neuroprotective, antidiabetic, immunomodulatory, osteoprotective, and gastroprotective properties of H. fusiformis extracts. Overall, further studies and strategies are required to develop H. fusiformis as a promising resource for the nutrition and pharmacological industries.

Comparative study of selective in vitro and in silico BACE1 inhibitory potential of glycyrrhizin together with its metabolites, 18α- and 18ß-glycyrrhetinic acid, isolated from Hizikia fusiformis.

Hizikia fusiformis (Harvey) Okamura is a brown seaweed widely used in Korea and Japan, and it contains different therapeutically active constituents. In the present study, we investigated the activities of glycyrrhizin isolated from H. fusiformis, including its metabolites, 18α- and 18ß-glycyrrhetinic acid against Alzheimer's disease (AD) via acetyl and butyrylcholinesterase and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibition. Among these three compounds, 18ß-glycyrrhetinic acid (IC50 = 8.93 ± 0.69 µM) demonstrated two fold potent activity against BACE1 compared to the positive control, quercetin (IC50 = 20.18 ± 0.79 µM). Additionally, glycyrrhizin with an IC50 value of 20.12 ± 1.87 µM showed similarity to quercetin, while 18α-glycyrrhetinic acid showed moderate activity (IC50 = 104.35 ± 2.84 µM). A kinetic study revealed that glycyrrhizin and 18ß-glycyrrhetinic acid were non-competitive and competitive inhibitiors of BACE1, demonstrated via K i values of 16.92 and 10.91 µM, respectively. Molecular docking simulation studies evidently revealed strong binding energy of these compounds for BACE1, indicating their high affinity and capacity for tighter binding to the active site of the enzyme. These data suggest that glycyrrhizin isolated from the edible seaweed, H. fusiformis and its metabolite, 18ß-glycyrrhetinic acid demonstrated selective inhibitory activity against BACE1 to alleviate AD.

Inhibitory Effect of Hizikia fusiformis Solvent-Partitioned Fractions on Invasion and MMP Activity of HT1080 Human Fibrosarcoma Cells.

Matrix metalloproteinases (MMPs) are endopeptidases that take significant roles in extracellular matrix degradation and therefore linked to several complications such as metastasis of cancer progression, oxidative stress, and hepatic fibrosis. Hizikia fusiformis, a brown algae, was reported to possess bioactivities, including but not limited to, antiviral, antimicrobial, and anti-inflammatory partly due to bioactive polysaccharide contents. In this study, the potential of H. fusiformis against cancer cell invasion was evaluated through the MMP inhibitory effect in HT1080 fibrosarcoma cells in vitro. H. fusiformis crude extract was fractionated with organic solvents, H2O, n-BuOH, 85% aqueous MeOH, and n-hexane (n-Hex). The non-toxicity of the fractions was confirmed by MTT assay. All fractions inhibited the enzymatic activities of MMP-2 and MMP-9 according to the gelatin zymography assay. Cell migration was also significantly inhibited by the n-Hex fraction. In addition, both gene and protein expressions of MMP-2 and -9, and tissue inhibitor of MMPs (TIMPs) were evaluated by reverse transcription-polymerase chain reaction and Western blotting, respectively. The fractions suppressed the mRNA and protein levels of MMP-2, MMP-9 while elevating the TIMP-1 and TIMP-2, with the H2O fraction being the least effective while n-Hex fraction the most. Collectively, the n-Hex fraction from brown algae H. fusiformis could be a potential inhibitor of MMPs, suggesting the presence of various derivatives of polysaccharides in high amounts.

Allelopathic interactions between the macroalga Hizikia fusiformis (Harvey) and the harmful blooms-forming dinoflagellate Karenia mikimotoi.

The effects of algal blooms on seaweeds have been rarely studied, although harmful algal blooms (HABs) are now normally regarded as worldwide incidents. In the present study, the effects of dense Karenia mikimotoi cells on the growth and photosynthesis of Hizikia fusiformis, a common and commercially cultivated macroalga in coastal waters of the East China Sea (ECS), were studied to understand the possible consequences when the mariculture encountered a dense harmful algal bloom. Furthermore, the counteraction of the latter on the growth and photosynthetic activities of K. mikimotoi was determined to evaluate the contribution of H. fusiformis commercial cultivation to environmental improvements. The results showed that the chlorophyll a (Chl a) contents, maximal photochemical efficiency (Fv/Fm) and relative electron transfer rate (rETR) of gas vesicles (specialized leaves), adult and young receptacles of H. fusiformis were all significantly (P<0.05) inhibited compared with the mono-cultured ones. When compared with mono-cultured H. fusiformis (without K. mikimotoi), the Chl a contents in gas vesicles, adult and young receptacles decreased by 20.6%, 17.6% and 33.2% within 2 weeks. Correspondingly, the Fv/Fm decreased by 7.9%, 37.4% and 43.7%; the apparent photosynthetic efficiency (α) decreased by 9.4%, 47.1% and 48.3%; and rETR decreased by 19.5%, 52.6% and 68.2%, respectively. The Chl a concentration of the mono-cultured K. mikimotoi (without H. fusiformis) increased to 2247.97µgl-1 from 958.11µgl-1 within 14 d. Those of the co-cultivated ones (with H. fusiformis), however, increased to 1591.31µgl-1 on the 8th day and then decreased rapidly to 254.99 (±37.73) µgl-1 after the next 6 days. Furthermore, compared with the mono-cultured K. mikimotoi cells, the Fv/Fm, α and rETRmax of co-cultivated ones decreased by 9.4%, 36.3% and 30.6%, respectively. The results indicated that the mature sporophytes of H. fusiformis were resistant to dense K. mikimotoi blooms and this resistance was organ-dependent as: gas vesicle>adult receptacles>young receptacles. On the other hand, commercial mariculture of H. fusiformis demonstrated the potential of preventing the occurrence of algal blooms.

Complete mitochondrial genome of the brown alga Sargassum fusiforme (Sargassaceae, Phaeophyceae): genome architecture and taxonomic consideration.

Sargassum fusiforme (Harvey) Setchell (=Hizikia fusiformis (Harvey) Okamura) is one of the most important economic seaweeds for mariculture in China. In this study, we present the complete mitochondrial genome of S. fusiforme. The genome is 34,696 bp in length with circular organization, encoding the standard set of three ribosomal RNA genes (rRNA), 25 transfer RNA genes (tRNA), 35 protein-coding genes, and two conserved open reading frames (ORFs). Its total AT content is 62.47%, lower than other brown algae except Pylaiella littoralis. The mitogenome carries 1571 bp of intergenic region constituting 4.53% of the genome, and 13 pairs of overlapping genes with the overlap size from 1 to 90 bp. The phylogenetic analyses based on 35 protein-coding genes reveal that S. fusiforme has a closer evolutionary relationship with Sargassum muticum than Sargassum horneri, indicating Hizikia are not distinct evolutionary entity and should be reduced to synonymy with Sargassum.

A novel thyroglobulin-binding lectin from the brown alga Hizikia fusiformis and its antioxidant activities.

A lectin (HFL) was isolated from the brown alga, Hizikia fusiformis, through ion exchange on cellulose DE52 and HPLC with a TSK-gel G4000PWXL column. SDS-PAGE showed that HFL had a molecular mass of 16.1 kDa. The HPLC (with a TSK-gel G4000PWXL column) indicated that HFL is a tetramer in its native state. The total carbohydrate content was 41%. Glucose, galactose and fucose were the monosaccharide units of HFL, and the normalized mol% values were 6, 14 and 80, respectively. HFL contains a large amount of the acidic amino acid, Asx. The ß-elimination reaction suggested that the oligosaccharide and peptide moieties of HFL may belong to the N-glucosidic linkage. The amino acid sequences, of about five segments of HFL, were acquired by MALDI-TOF/TOF, and the sequences have no homology with other lectins. HFL was found to agglutinate sheep erythrocytes. The hemagglutination activity was inhibited by thyroglobulin, from bovine thyroid, but not by any of the monosaccharides tested. The lectin reaction was independent of the presence of the divalent cation Ca(2+). HFL showed free radical scavenging activity against hydroxyl, DPPH and ABTS(+) radicals.

Hizikia fusiformis fractions successfully improve atopic dermatitis indices in anti-CD3-stimulated splenocytes and 2,4-dinitrochlorobenzene-treated BALB/c mice.

OBJECTIVES: In the present study, we aimed to examine whether fractions from an edible sea weed, Hizikia fusiformis, had immunomodulatory effects, particularly an anti-atopic effect, by attenuating the expression of T cell-dependent cytokines using in-vitro and in-vivo animal atopic dermatitis-like models. METHODS: The anti-atopic activities were examined in in vitro, and a 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis-like mouse model using quantitative real-time polymerase chain reaction, electrophoretic-mobility shift and histopathological analysis. KEY FINDINGS: Our results showed that the final fraction (F2') of H. fusiformis contained a higher amount of butanoic acid which was not found in the other fractions, and effectively inhibited T cell activation by inhibiting dephosphorylation of nuclear factor of activated T cells in electrophoretic-mobility shift assay. As a consequence, helper T cell-dependent cytokines, such as interleukin-2, -4 and interferon-γ, were significantly inhibited while activated with an anti-CD3 antibody. We also showed that skin challenged with DNCB successfully recovered when treated with 2.5 mg/kg, comparable to that by 0.25% prednicarbate. These results indicate that F2' may contribute to inhibit T cell activation by eliminating Th cell-dependent cytokines. CONCLUSIONS: Taken together, we concluded that F2' containing butanoic acid may be a new functional anti-atopic candidate, which probably acts through nuclear factor of activated T cell inactivation mechanisms.

SHORT- AND LONG-TERM EFFECTS OF ELEVATED CO2 ON PHOTOSYNTHESIS AND RESPIRATION IN THE MARINE MACROALGA HIZIKIA FUSIFORMIS (SARGASSACEAE, PHAEOPHYTA) GROWN AT LOW AND HIGH N SUPPLIES(1).

The short-term and long-term effects of elevated CO2 on photosynthesis and respiration were examined in cultures of the marine brown macroalga Hizikia fusiformis (Harv.) Okamura grown under ambient (375 µL · L(-1) ) and elevated (700 µL · L(-1) ) CO2 concentrations and at low and high N availability. Short-term exposure to CO2 enrichment stimulated photosynthesis, and this stimulation was maintained with prolonged growth at elevated CO2 , regardless of the N levels in culture, indicating no down-regulation of photosynthesis with prolonged growth at elevated CO2 . However, the photosynthetic rate of low-N-grown H. fusiformis was more responsive to CO2 enrichment than that of high-N-grown algae. Elevation of CO2 concentration increased the value of K1/2 (Ci) (the half-saturation constant) for photosynthesis, whereas high N supply lowered it. Neither short-term nor long-term CO2 enrichment had inhibitory effects on respiration rate, irrespective of the N supply, under which the algae were grown. Under high-N growth, the Q10 value of respiration was higher in the elevated-CO2 -grown algae than the ambient-CO2 -grown algae. Either short- or long-term exposure to CO2 enrichment decreased respiration as a proportion of gross photosynthesis (Pg) in low-N-grown H. fusiformis. It was proposed that in a future world of higher atmospheric CO2 concentration and simultaneous coastal eutrophication, the respiratory carbon flux would be more sensitive to changing temperature.