Tumor nodules (tn) have been histologically identified within the fatty tissue or the detached fatty tissue around dissected lymph nodes, or else picked up as lymph nodes from resected specimens with ...no lymph node components. The TNM classification of malignant tumors provides a description of how to deal with tn, but there has so far been no description within the Japanese classification of colorectal carcinoma. The aim of this study was to determine whether we should regard tn as metastatic lymph nodes from the viewpoint of prognosis.
A total of 544 patients who underwent a resection of colorectal adenocarcinoma between 1985 and 1995 were reviewed.
Tumor nodules were found in 54 (17.6%) of 307 colon cancer patients, and in 41 (17.3%) of 237 rectal cancer patients. We classified the curability A patients into four groups for both colon and rectal cancer; positive lymph nodes with tn (Group A), negative lymph nodes with tn (Group B), positive lymph nodes without tn (Group C), and negative lymph nodes without tn (Group D). The prognosis was not significantly different between Groups A, B, and C, but it was significantly different between Group D and Groups A, B, and C (P < 0.01) in both the colon and the rectum.
From the viewpoint of prognosis, it thus appears justifiable to regard tn as lymph node metastasis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Fucoidan, a series of natural high-molecular weight sulfated polysaccharides derived from brown algae, has been reported to have various physiological effects such as antitumor, antiviral, ...and immunomodulatory activities. In a previous study, we demonstrated that fucoidan from Cladosiphon okamuranus (Okinawamozuku) was effectively activate murine macrophage-like cell line RAW264 in synergistic action with dectin-1-stimulating beta-glucan from Saccharomyces cerevisiae. In this study, we further examined their synergistic mode of action of Okinawamozuku-derived fucoidan in cooperate with pathogen stimulation in terms of dendritic cell activation. After myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC) were differentiated by culturing bone marrow cells isolated from C57BL/6J mice with Flt3 ligand, cytokine production upon stimulation with fucoidan and various pathogen components (pattern recognition receptor, PRR ligands) was measured. As the results, fucoidan alone enhanced the production of interferon (IFN)-gamma by the Flt3-L-induced mixed BMDCs, and besides, fucoidan synergistically augmented IFN-gamma production with Pam3CSK4 (bacterial TLR1/TLR2 ligand) or Poly(I:C)/LyoVec (viral RIG-I ligand). On the other hand, their IFN-alpha productions were reinforced with Poly(I:C) (viral TLR3 ligand), ODN1585 (viral TLR9 ligand) and Poly(I:C)/LyoVec, although no synergic enhancement by fucoidan was observed. These results suggested that fucoidan was extremely effective in activating dendritic cells, which play a central role in the regulation of immune function to eliminate infectious pathogens.
Supported by grants from JSPS KAKENHI (JP21K05423)
Abstract
Fucoidan is a series of natural sulfated polysaccharides derived from brown seaweeds and have reported to possess various biological activities such as anti-tumor, anti-virus, and ...immuno-modulatory effects. In previous study, we revealed that fucoidan derived from Cladosiphon okamuranus activated murine macrophage-like cell line RAW264 cooperatively with Zymosan, a Saccharomyces cerevisiae-derived β-glucan. On the other hand, several reports demonstrated that fucoidan inhibited lipopolysaccharide (LPS)-induced production of nitrogen oxide (NO) and inflammatory cytokines by RAW264 cells. Therefore, in this study, we investigated the potential of fucoidan derived from Undaria pinnatifida to regulate the excessive activation of RAW264 cells in response to overstimulation with pathogen components. RAW264 cells were inoculated at 20000 cells/well in 96-well culture plates, and after a recovery culture for 24 hr, the cells were treated with fucoidan with or without appropriate concentrations of each ligand for pattern recognition receptors (PRRs) including Toll-like receptors (TLRs). Whereas the production of NO was significantly enhanced with fucoidan alone, it was dose-dependently inhibited by fucoidan under stimulation with Pam3CSK4 (TLR1/TLR2 ligand), heat killed Listeria monocytogenes (HKLM, TLR2 ligand), LPS (TLR4 ligand), Pam2CGDPKHPKSF (FSL-1, TLR2/TLR6 ligand). These results suggested that fucoidan have beneficial ability to alleviate excessive inflammatory reaction during pathogenic infection and maintain suitable immune balance.
Supported by Laboratory of Analytical Food Immunoscience belonging YM is a donated fund laboratory established in Faculty of Agriculture, Kyushu University by Ventuno Co., Ltd.
Abstract
Fucoidan is a series of natural sulfated polysaccharides contained in brown sea algae, and their beneficial physiological activities such as anti-tumor, anti-virus and immune regulatory ...effects have been reported. In previous studies, we proved that fucoidans derived from Cladosiphon okamuranus (C. okamuranus) and Undaria pinnatifida effectively improved anti-tumor immunity and tumor vaccine efficiency in combination with an Agaricus blazei mycelium extract. It is thought that the fucoidan-agaricus mix (named fucoidan-mix AG) stimulate innate immune cells to activate intestinal and mucosal immune reaction, but actual target immune tissues and cells by fucoidan have not been evidenced yet. In this study, we investigated action mechanisms of fucoidan in regulation of mucosal immune activities. At first, immune cells were isolated from Payer’s patches, mesenteric lymph node (MLN) and intestinal epithelia of Balb/c mice, then stained with fluorophore-labeled fucoidan. As the results, it was revealed that fucoidan directly interact with lymphocytes besides dendritic cells and macrophages existing in these intestinal immune tissues. Furthermore, immune cells from Payer’s patches and MLN stimulated with fucoidan from C. okamuranus and fucoidan-mix AG produced more TNF-α, IL-12 and Th1 cytokine IFN-γ. The production of an immunosuppressive cytokine IL-10 also was augmented in the fucoidan-treated immune cells, which suggesting that fucoidan balanced immune system to prevent occurrence of excessive reaction. In addition, it was newly proved that fucoidan directly stimulated T lymphocytes to induce enhanced IFN-γ production.
Purpose
We introduced a new concept of
ex vivo
gene expression analysis (Mitsuhashi,
Clin Chem
53:148–149, 2007), where drug action was simulated under physiological conditions. This model system was ...applied to study various fields of drug development.
Materials and Methods
Heparinized human whole blood was incubated with drugs for less than 4h. The changes of specific mRNA were then quantified using the method we developed (Mitsuhashi, Tomozawa, Endo, and Shinagawa,
Clin Chem
52:634–642, 2006).
Results
The mRNA quantitation method was used as a model system to study the following areas: (1) identification of respondents and non-respondents, (2)
ex vivo
compound screening, (3) determination of individually optimized doses, (4) drug-to-drug comparison, (5) assessment of leukocyte toxicity, (6) discovery of molecular targets, (7) assessment of the action of dietary supplements, and (8) characterization of respondents and non-respondents for various dietary supplements.
Conclusion
Since
ex vivo
assays are safe, a large number of healthy donors and disease patients can be recruited to identify individual-to-individual variations, which is not available from current preclinical study models. Although each system should be validated using a large number of samples, the
ex vivo
analysis will be a new tool for the development of drugs and dietary supplements in future.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Fucoidan is a series of natural sulfated polysaccharides contained in brown sea algae. In previous studies, we proved that fucoidans derived from Cladosiphon okamuranus and Undaria ...pinnatifida effectively augmented anti-tumor immunity in combination with an Agaricus blazei mycelium extract. In this study, we evaluated dietary effects of the mixture consist of the two high-molecular weights fucoidan and the agaricus extract (named CUA-fucoidan) on tumor angiogenesis. For that purpose, C57BL/6 mice were subcutaneously injected basement membrane matrix (Geltrex) enclosing 5×104 mitomycin C-treated B16 melanoma cells or 500 ng/mL vascular endothelial growth factor (VEGF), and fed 2% CUA-fucoidan containing diet for 7 days before and after the matrix inoculation. The accumulation of hemoglobin and CD31-positive cells in the B16-enclosed Geltrex was lower in the CUA-fucoidan-fed mice than in the control mice, whereas the hemoglobin contents in the VEGF-enclosed Geltrex were not affected by the CUA-fucoidan feeding. These results suggested that CUA-fucoidan was effective in suppressing tumor angiogenesis, but did not inhibit the physiological action of VEGF. Rather, it was guessed that CUA-fucoidan suppressed VEGF production because the expression of VEGF mRNA was reduced in the matrix resected from CUA-fucoidan-fed mice. In this context, the infiltration of CD206-positive macrophages, which known to produce VEGF, were declined by the CUA-fucoidan feeding. Furthermore, CUA-fucoidan decreased accumulation of Treg in the B16-included Geltrex, and delayed B16 tumor growth. In conclusion, CUA-fucoidan was expected to be effective in inhibition of tumor angiogenesis by improving immunosuppressive tumor microenvironments.
The present study investigated immune stimulatory effects of Cladosiphon okamuranus-derived fucoidan to activate murine macrophage-like cell line RAW264, and the functional relationship with zymosan, ...a Saccharomyces cerevisiae-derived β-glucan. The production of nitric oxide (NO) and tumor necrosis factor-α (TNF-α) in RAW264 cells were remarkably enhanced in the presence of 10 μg/mL fucoidan, and the stimulatory effects of fucoidan were maximally augmented in combinational treatment with 500 ng/mL zymosan, whereas any TLR ligands had no those effects. Confocal microscopic analyses suggested that fucoidan bound on plasma membrane, and it was estimated that some cell surface molecules acted as receptor for fucoidan because cytochalasin D, an inhibitor of phagocytosis, did not affect the immune enhancing activities, whereas methyl-β-cyclodextrin (MβCD), a general agent for disruption of lipid rafts, diminished that. Furthermore, it was revealed that the additive effects of zymosan on the immune activation with fucoidan was thought to be mediated by dectin-1 based on the results with dectin-1-knockdown RAW264 cells. All of results suggested that fucoidan and some kinds of β-glucan would cooperatively reinforce the activity of innate immune cells via interactive receptor crosstalk.
•Fucoidan is a series of unique bioactive polysaccharides have immuno-stimulating activities.•Fucoidan have physiological function to augment Th1 immune responses and activities of natural killer (NK) cells.•Fucoidan have ability to modulate macrophages through stimulation to TLR2, TLR4 (CD14) and class A scavenger receptor.•Dectin-1, a receptor for β-glucan synergizes with TLR2 and TLR4 to enhance functions of macrophages and dendritic cells.•Fucoidan and β-glucan are expected to application into prevention or treatment support of infectious diseases and cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Fucoidan is a series of sulfated polysaccharides derived from brown algae that mainly consist of L-fucose. Various biological activities of fucoidan such as anti-cancer and immune modulatory ...effects were reported, and our investigation with animal experiments and human trials demonstrated fucoidan from Cladosiphon okamuranus and Undaria pinnatifida effectively augmented anti-tumor immunity in combination with Agaricus blazei mycelium extract. In this study, we evaluated dietary effects of the two types of high-molecular weight fucoidans and the agaricus extract mix (CUA) on achievement of effective tumor vaccination with a tumor antigen gp70 expressed on colon-26 tumor cell line. Balb/c mice were immunized with 0.05 mg gp70 peptide emulsified in complete freund’s adjuvant and intake 1% CUA containing AIN93G diet for 4 weeks. This procedure totally enhanced systemic immune function because splenocytes from the vaccinated mice extensively proliferate in response to concanavalin A-stimulation. The NK cell activity and gp70 peptide-stimulated IFN-gamma production in splenocytes from the vaccinated mice were tended to augment by the CUA feeding. On the other hands, the CUA feeding potentiated the killing activity to colon-26 carcinoma of draining lymph node (LN) cells from the vaccinated mice in association with increase of gp70-specific CD8-positive T cell population. Furthermore, the expressions of MHC class II molecule (I-A/I-E) on CD11c-positive and F4/80-positive populations of LN cells from the vaccinated mice were elevated by the intake of CUA. These results suggested that the CUA feeding potentially support effective induction of anti-tumor immune function by vaccination with tumor antigen peptides.
Abstract
Fucoidan is a series of sulfated polysaccharides derived from brown algae, and have reported to have various biological activities. Previously, we demonstrated that fucoidan derived from ...Cladosiphon okamuranus and Undaria pinnatifida effectively augmented anti-tumor immunity in combination with Agaricus blazei mycelia extract. In this study, we evaluated the capacity of the fucoidan-agaricus mix (FAM) to enhance oral mucosal immune function. Fifteen healthy volunteers (mean age, 41.2 years old; range, 22–56 years old; 8 males, 7 females) ingested 4 capsules each containing 250 mg FAM powder every day for 12 weeks. As a result, the mean of secretory rates of salivary secretory immunoglobulin A (sIgA) tended to be increased by the FAM administration for 4 and 12 weeks as compared with the initial value. The enhanced salivary sIgA secretion was more distinctly observed in subject group whose initial values of salivary sIgA secretory rate were lower than the total average. Furthermore, the intake of FAM led to significant augmentation in the salivary sIgA secretion (by 1.3-fold) in the group of subjects under 40 years of age. On the other hand, concanavalin A-induced blastogenic response of peripheral blood mononuclear cells and serum IgA concentration was not elevated during this trial. Therefore, it was suggested that FAM stimulated functional maturation rather than expansion of B lymphocyte. The intake of FAM did not significantly affect NK cell activities. In addition, the safety of FAM consumption was confirmed because no abnormal findings were observed in general clinical tests. From the results, it was suggested that intake of FAM was useful in augmentation of oral mucosal immune defense via enhancing salivary sIgA production.
Abstract
Fucoidan is a series of sulfated polysaccharides derived from brown algae that mainly consist of L-fucose. Fucoidan have various biological activities, and our investigation with ...experimental animal models and a healthy human trial demonstrated fucoidan from Cladosiphon okamuranus and Undaria pinnatifida effectively augmented anti-tumor immunity in combination with agaricus mycelium extract. In this context, we have reported that feeding of the fucoidan-agaricus mix (FAM) protected mice from immunosuppressive effect of 5-fluorouracil (5-FU). In current study, we confirmed dose-dependent immunoprotective effects of the dietary FAM (at 20 and 40 mg/day) by observing recovery in spleen weight, NK cell activity and IFN-γ production in 5-FU-treated mice. Furthermore, we investigated in vitro effects of FAM against 5-FU on growth and function of primary cultured immune-related cells. As the results with thioglycollate-induced peritoneal exudates cells (PEC), 5-FU dose-dependently suppressed the growth whereas FAM exerted no effects. However, production of cytokines such as IL-12p40 and TNF-α in PEC were stimulated by FAM treatment even in the presence of 5-FU. In the case of bone marrow derived cells differentiated with GM-CSF and M-CSF, FAM markedly enhanced the growth and IL-12 production of these cells. From these results, it was suggested that FAM contributed to amelioration of decline in anti-tumor immune function by 5-FU treatment through activation of innate immune cells.
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