Induction of antigen-specific immune activation by the maturation of dendritic cells (DCs) is a strategy used for cancer immunotherapy. In this study, we find that FimH, which is an Escherichia coli ...adhesion portion, induces toll-like receptor 4-dependent and myeloid differentiation protein 2-independent DC maturation in mice in vivo. A combined treatment regimen with FimH and antigen promotes antigen-specific immune activation, including proliferation of T cells, production of IFN-γ and TNF-α, and infiltration of effector T cells into tumors, which consequently inhibits tumor growth in mice in vivo against melanoma and carcinoma. In addition, combined therapeutic treatment of anti-PD-L1 antibodies and FimH treatment efficiently inhibits CT26 tumor growth in BALB/c mice. Finally, FimH promotes human peripheral blood DC activation and syngeneic T-cell proliferation and activation. Taken together, these findings demonstrate that FimH can be a useful adjuvant for cancer immunotherapy.
Anticancer drug‐mediated induction of immunogenic cell death (ICD) blocks metastasis or recurrence in cancer cells by promoting specific immune activity against cancer antigens. However, this ...strategy has failed to afford adequate treatment efficiency. Overcoming the failure of ICD‐mediated cancer therapy, lipid nanoparticles (LNPs) containing cancer cell surface proteins are synthesized using sonication and extrusion without microfluidics. In addition, these LNPs are decorated with high‐mobility group box 1 protein and calreticulin, indicators of ICD, and named artificial ICD LNPs (AiLNPs). Administration of AiLNPs effectively targets dendritic cells (DCs) and induces DC activation in mice. Moreover, treating CT‐26 tumor‐bearing mice with AiLNPs inhibits tumor growth by inducing CT‐26 antigen‐specific T‐cell immunity. Furthermore, AiLNPs containing Lewis lung carcinoma (LLC1) membrane proteins can prevent metastatic LLC1 tumor growth in the lung via LLC1 antigen‐specific T‐cell activation. Finally, AiLNPs synthesized with human breast cancer membrane proteins activate DC‐mediated antigen‐specific T‐cell immunity, effectively killing tumor cells. Therefore, AiLNPs are expected to be developed as a patient‐specific cancer treatment to prevent cancer recurrence and metastasis.
Schematic illustration of Artificial immunogenic cell death lipid nanoparticles (AiLNPs)‐mediated cancer immunotherapy. AiLNP elicits activation and maturation of conventional dendritic cell1 (cDC1) and cDC2 in humans and mice. AiLNP‐induced activation of DCs promotes tumor antigen‐specific helper and cytotoxic T‐cell activation, which further promotes anticancer immunity against colon and lung carcinoma.
AbstractA seismic retrofit method using external steel frames was studied for old RC buildings with nonseismic details. To verify the external retrofit method, 2-story frame specimens were tested ...under cyclic lateral loading. The test results indicated that the external steel frame successfully enhanced the stiffness and strength of deficient RC moment frames without deteriorating the deformation capacity. The energy-dissipation capacity was also improved by restraining early failure of the RC beam-column joints. The failure mode of the retrofitted frames was governed by the flexural mechanism of the first-story RC columns, with partial yielding of the upper structure. The RC columns were subjected to additional axial forces that were transferred from the external steel frame, in which the steel columns were not extended to the foundation. The strengths of retrofitted frames were evaluated by two approaches based on the frame plastic hinge mechanism: (1) the sum of the strengths of independent RC and steel moment frames, and (2) the strength assuming full composite section of concrete and steel members. On the basis of the test results, design considerations for the external steel frame-retrofitting method are recommended.
Cigarette smoke induces an inflammatory response in the lungs by recruiting inflammatory cells, leading to lung diseases such as lung cancer, chronic obstructive pulmonary disease, and pulmonary ...fibrosis. Existing inhalation exposure methods for assessing the adverse effects of cigarette smoke require expensive equipment and are labor‐intensive. Therefore, we attempted to develop a novel method to assess these adverse effects using intratracheal instillation (ITI) of whole cigarette smoke condensate (WCSC). The WCSC (0, 5, 10, or 20 mg/mL) was administered by ITI once daily for 6 or 12 days using an automatic video instillator. Repeated WCSC ITI increased the lung weight, and monocyte chemoattractant protein‐1 (MCP‐1), neutrophil, and lymphocyte levels within bronchoalveolar lavage fluid compared to the control. In the histopathological analysis of the lung tissue, a mild inflammatory response was observed in the 6 and 12 days 20 mg/mL WCSC exposure groups. The genome‐wide RNA‐seq expression patterns revealed that inflammatory and immune response‐related genes, such as the chemokine signaling pathway, Th1/Th2 cell differentiation, and cytokine‐cytokine receptor interaction, were employed following WCSC exposure. In addition, MCP‐1 was time‐dependent and increased in the 10 mg/mL exposure group compared to the control group. These results suggested that the WCSC might induce the potential pulmonary inflammatory response. Furthermore, we proposed that ITI may be a rapid and effective method of evaluating the adverse effects of WCSC within a short exposure period (less than 2 weeks), and it can be used to evaluate cigarette inhalation toxicity studies as an alternative method.
Drosophila melanogaster (D. melanogaster) is a promising model biological system. It has a short life cycle and can provide a substantial number of specimens suitable for comprehensive genetic and ...molecular analyses in a short time. In this study, we investigated the acute inhalation toxicity of methylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT) in a D. melanogaster model. During exposure, environmental conditions, mass median aerodynamic and geometric standard diameters were measured. After inhalation exposure, the survival rate, climbing ability, and bang sensitivity were measured on days 1, 2, and 7. Notably, the survival rate of flies decreased in an exposure concentration-dependent manner. Climbing ability and bang sensitivity were also altered in the MIT/CMIT group, compared with the negative control group. Overall, these results provide a reliable D. melanogaster model system for inhalation toxicity study.
AbstractAn internal steel frame–retrofitting method without diagonal braces was studied to strengthen existing reinforced-concrete (RC) moment frames with nonseismic details. For better ...constructability and structural capacity, a novel shear connection method was developed and verified by cyclic shear testing. To evaluate the seismic performance of retrofitted frames, three two-story moment frames with and without strengthening were tested under cyclic lateral loading. The test results showed that, despite partial composite action between RC and steel members, the proposed retrofit method significantly increased the stiffness and strength of the RC moment frame, achieving a satisfactory deformation capacity greater than 2% drift ratio. On the basis of the test results, the failure mechanism of the retrofitted frame was discussed, considering the shear connection behavior. The test strengths of the frame specimens were compared with the predictions based on a simple plastic mechanism. Further, the degree of partial composite action between the RC and steel members developed by shear connections was addressed to improve the strength predictions.
•P. yezoensis porphyran inhibits LPS-induced DC activation in vitro and in vivo.•LPS-induced IFN-γ-producing Th1 and Tc1 cell differentiation was inhibited by porphyran.•Porphyran interrupted LPS ...binding to DCs in mouse.
We previously demonstrated that porphyran, a sulfated polysaccharide extracted from Pyropia yezoensis, shows protective effects on LPS-induced septic shock in the mouse. However, the immune cell-mediated inhibitory effect of porphyran in LPS-induced activation of immune cells has not been well investigated. In this study, we found that treatment of porphyran suppressed LPS-induced upregulation of costimulatory molecule and C-C chemokine receptor type 7 (CCR7) expression in bone marrow-derived dendritic cells (BMDCs) in vitro and spleen DCs in vivo. Moreover, the LPS-induced expression of IL-6, IL-12, and TNF-α in the culture medium of BMDCs and serum dose-dependently decreased by porphyran treatment, which contributed to the inhibition of the intracellular cytokine production in spleen DCs. In addition, LPS-induced differentiation of helper T1 (Th1) and cytotoxic T1 (Tc1) cells was effectively suppressed by porphyran treatment in mice. The inhibitory effect of porphyran in LPS-induced immune activation was mediated by competitive binding of porphyran with LPS in spleen DCs. Thus, these results suggest that porphyran is a promising potential therapeutic agent in endotoxin-mediated inflammatory disease and septic shock.
Laminaria japonica is a brown alga and is composed primarily of polysaccharides. Fucoidan and laminarin are the major polysaccharides of L. japonica and exhibit biological activities, including ...immune modulation and anti-coagulant and antioxidant effects in animals and humans. In this study, we evaluated the ability of fucoidan and laminarin from L. japonica to induce immune cell activation and anti-cancer immunity, which has not yet been studied. The injection of fucoidan to mice promoted the upregulation of major histocompatibility complex and surface activation molecules in splenic dendritic cell subsets, whereas laminarin showed a weaker immune activation ability. In addition, fucoidan treatment elicited inflammatory cytokine production; however, laminarin did not induce the production of these cytokines. Regarding cytotoxic cell activities, fucoidan induced the activation of lymphocytes, including natural killer and T cells, whereas laminarin did not induce cell activation. Finally, fucoidan enhanced the anticancer efficacy of anti-programmed Death-Ligand 1 (PD-L1) antibody against Lewis lung carcinoma, whereas laminarin did not promote the cancer inhibition effect of anti-PD-L1 antibody. Thus, these data suggest that fucoidan from L. japonica can be used as an immune stimulatory molecule to enhance the anticancer activities of immune checkpoint inhibitors.
•Fucoidan from L. japonica have a stronger effect on DC activation than Laminarin from L. japonica.•Fucoidan elicits inflammatory cytokine production but the laminarin did not induce any production of those cytokines•Fucoidan induces the activation of NK cells and T cells, whereas laminarin did not.•Fucoidan enhances the anticancer efficacy of anti-PD-L1 antibody against lewis lung carcinoma.
Fucoidan is known to exert immunomodulatory effects in animals and humans. Here, we extracted fucoidan from Ecklonia cava (ECF) and evaluated its immunostimulatory and anticancer activities in mice. ...Treatment with ECF resulted in the activation of bone marrow-derived dendritic cells (BMDCs) in vitro and splenic DCs in vivo. Moreover, the combination of ECF and ovalbumin (OVA) promoted OVA-specific T cell proliferation and cytokine production, which consequently suppressed B16-OVA tumor growth in vivo. The combination treatment with ECF and carcinoma self-antigen resulted in the inhibition of the growth of CT-26 carcinoma in mice through carcinoma antigen-specific immunity. Thus, ECF could function as an adjuvant for the induction of anticancer immunity.
•ECF induces activation of mouse DCs in vitro and in vivo.•ECF promotes antigen-specific T cell immunity in mouse in vivo.•Combination treatment of ECF and cancer antigen suppresses tumor growth in mouse.
Natural polysaccharides exhibit beneficial immune modulatory effects, including immune stimulatory and anti-cancer activities. In this study, we examined the effect of
polysaccharide (CFP) on natural ...killer (NK) cell activation, and its effect on tumor-bearing mice. Intravenous CFP treatment of C57BL/6 mice resulted in the upregulation of CD69, which is a marker associated with NK cell activation. In addition, intracellular levels of interferon (IFN)-γ and the cytotoxic mediators perforin and granzyme B were markedly increased in response to the CFP treatment of splenic NK cells. IFN-γ production by NK cells was directly induced by CFP, whereas the upregulation of CD69 and cytotoxic mediators required IL-12. Finally, intraperitoneal treatment with CFP prevented CT-26 (murine carcinoma) tumor cell infiltration in the lungs, without significantly reducing the body weight. In addition, treatment with CFP prevented B16 melanoma cell infiltration in the lung of C57BL/6 mice. Moreover, the anti-tumor effect was diminished by the depletion of NK cells. Therefore, these data suggest that CFP may be used as an NK cell stimulator to produce a phenomenon that contributes to anti-cancer immunity.
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