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.
본 연구는 대 플리니우스의 『자연사』 속 정원 관련 문헌을 중심으로 고대 로마 시대의 정원관을 탐색함을 목표로 한다. 고대 로마 정원의 유형과 성격, 형태 등은 이후 서양 정원의 발달에 큰 영향을 미쳤고, 플리니우스 등이 집필한 실용적이고 전문적인 문헌이 큰 영향을 미쳤다. 『자연사』와 관련 문헌, 사료를 중심으로 진행된 본 연구에서는 로마 정원의 형태나 ...양식적 특징에 대한 이해를 바탕으로, 이들 문헌에 투영된 정원관을 탐색하였다. 『자연사』뿐 아니라 고대 로마 시대에 작성된 정원, 혹은 농업 이론서는 관념적인 자연이나 예술로서의 정원보다는 실용적인 생산 공간을 주로 다룬다는 특징이 있다. 『자연사』에서 정원 연구와 관련된 식물학 부분 또한 즐거움보다는 유용함을 위주로 기술되었고, 플리니우스 또한 실용적인 정원인 호르투스를 전제로 논의를 전개하였다. 고대 로마 사회에서 정원은 실용적인 생산과 휴식의 공간일 뿐 아니라, 한 시대의 이상을 재현, 혹은 실천하는 장소였다. 플리니우스를 비롯한 로마의 지배세력과 지식인들은 그들이 지배하는 전 세계에 대한 앎을 포괄하고, 이를 통해 로마 대제국의 비전을 실현하고자 하는 에피스테메를 공유했다. 플리니우스는 『자연사』를 통해 당대의 유용한 지식을 로마 제국이라는 방대한 문명 세계로 포괄하고자 했고, 정원은 그 이상을 실천하는 중요한 장소였다.
This study investigates the garden vision of the Ancient Rome, focusing on garden literature in the Natural History by Pliny the Elder. Ancient Roman garden’s types, character, and forms greatly influenced the development of later Western gardens, to which the practical and professional texts of Pliny the Elder and others contributed. This study explores the garden visions projected in these texts, with an introduction of Roman garden forms and stylistic features. The Natural History and other garden and agricultural texts written during the Ancient Roman period are characterized by their focus on practical production spaces rather than abstract nature or garden art. In the Natural History, Pliny described botanics in terms of usefulness rather than pleasure, and his discussion is premised on the practical hortus. In ancient Roman society, gardens were not only spaces for practical production and relaxation, and places to reproduce or realize the ideals of Roman rulers and intellectuals, including Pliny. They shared the episteme that sought to encompass knowledge of the entire world they ruled and, in doing so, realize their vision of the Roman Empire. Through the Natural History, Pliny sought to embrace useful knowledges of his time into the vast civilized world of the Roman Empire, and the garden was an important place to practice this ideal.
Melanoma is the most lethal form of skin cancer because it spreads easily to other tissues, thereby decreasing the efficiency of its treatment via chemo-, radio-, and surgical therapies. We suggest ...the application of an attachable hydrogel for the treatment of melanoma whereby the size and amount of incorporated indocyanine green (ICG) for photothermal therapy (PTT) can be controlled. An attachable hydrogel (poly(acrylamide-co-diallyldimethylammonium chloride); PAD) that incorporates ICG as a near-infrared (NIR) absorber was fabricated using a biocompatible polymer. The temperature of PAD-ICG increases under 808 nm laser irradiation. The hydrogel protects the ICG against decomposition; consequently, PAD-ICG can be reused for PTT. The attachment of PAD-ICG to an area with melanoma in mice, with irradiation using a NIR laser, successfully eliminated melanoma. Thus, the data suggest that PAD-ICG is a smart material that could be used for selective target therapy against melanoma in humans.
Monophosphoryl lipid A (MPLA) is a toll-like receptor 4 ligand that promotes immune activation in mice and humans, without undesired inflammation. Immunotherapy by the combining immune checkpoint ...blockade and MPLA has shown promising anti-cancer effects in both mice and humans. In this study, we explored how MPLA enhanced the anti-cancer effects of anti-PD-L1 antibodies (Abs). Anti-cancer immunity induced by the combination of anti-PD-L1 Abs and MPLA failed in CD4 and CD8 cell-depleted mice. Moreover, the combination treatment of anti-PD-L1 Abs and MPLA synergistically enhanced the activation of plasmacytoid dendritic cells (pDCs) in the mouse in vivo, while conventional DCs were not. In addition, mice treated with anti-PD-L1 Abs and MPLA were not protected from B16 melanoma by blockade of interferon-alpha receptor (IFNAR). The combination of anti-PD-L1 Abs and MPLA also promoted human peripheral blood pDC activation and induced IFN-α-dependent T cell activation. Therefore, these results demonstrate that MPLA enhances anti-PD-L1 Ab-mediated anti-cancer immunity through the activation and IFN-α production of pDCs.
•Pyropia yezoensis porphyran inhibits LPS-induced proinflammatory cytokines in human PBMCs.•Porphyran suppresses LPS-induced human MODC and PBDC activation.•LPS binding to TLR4/MD2 complex is ...interrupted by porphyran in human PBDCs.
In mice, porphyran extracted from Pyropia yezoensis exerts anti-inflammatory effects and suppresses lipopolysaccharide (LPS)-induced immune activation and sepsis. Here, we investigated inhibition of LPS-induced activation of human immune cells by porphyran and the underlying mechanisms. We demonstrated that porphyran may inhibit LPS-induced proinflammatory cytokine production in peripheral blood mononuclear cells, monocyte-derived dendritic cells, and peripheral blood dendritic cells. We also observed that porphyran-mediated LPS-induced activation of DC suppressed syngeneic T cell proliferation, resulting in reduced production of interferon-γ. The mechanism of LPS-induced immune cell activation requires the activation of toll like receptor 4 following binding of LPS to myeloid differentiation factor 2 (MD2). Additionally, we show that porphyran competes with LPS for binding to MD2 and thereby suppresses immune cell activation. Porphyran may, therefore, be a promising therapeutic candidate for the treatment of endotoxin-mediated septic shock and inflammation in humans.
Immunotherapies have been gaining attention for the prevention of cancer recurrence and metastasis. Cancer immunotherapy can induce memory cells to target cancer-specific antigens and, thus, ...selectively kill cancer cells. However, there are difficulties in inducing cancer antigen-specific immunity due to limited knowledge regarding cancer antigens. In this study, we synthesized a dual-functional hydrogel to induce antigen generation and immune activation.
To elicit a cancer self-antigen-specific immune response, we synthesized an alginate-collagen-based injectable hydrogel, called thermally responsive hydrogel (pTRG), which was incorporated with indocyanine green and the immune stimulator polyinosinic:polycytidylic acid (poly I:C). pTRG was evaluated for its anticancer and anti-metastatic effects against CT-26 carcinoma and 4T1 breast tumor in mice by combining photothermal therapy (PTT) and immunotherapy. Near-infrared (NIR) irradiation promoted temperature elevation in pTRG, consequently exerting a therapeutic effect on mouse tumors. Lung metastasis was prevented in cured CT-26 tumor-injected mice following pTRG treatment via cancer antigen-specific T cell immunity. Moreover, pTRG successfully eliminated the original tumor in 4T1 tumor-bearing mice via PTT and protected them from lung metastasis. To further evaluate the carrier function of TRGs, different types of immunotherapeutic molecules were incorporated into TRGs, which led to the effective elimination of the first CT-26 tumor and the prevention of lung metastasis.
Our data demonstrate that TRG is a efficient material not only for treating primary tumors but also for preventing metastasis and recurrence.
Although fucoidan, a well-studied seaweed-extracted polysaccharide, has shown immune stimulatory effects that elicit anticancer immunity, mucosal adjuvant effects via intranasal administration have ...not been studied. In this study, the effect of
-extracted fucoidan (ECF) on the induction of anti-cancer immunity in the lung was examined by intranasal administration. In C57BL/6 and BALB/c mice, intranasal administration of ECF promoted the activation of dendritic cells (DCs), natural killer (NK) cells, and T cells in the mediastinal lymph node (mLN). The ECF-induced NK and T cell activation was mediated by DCs. In addition, intranasal injection with ECF enhanced the anti-PD-L1 antibody-mediated anti-cancer activities against B16 melanoma and CT-26 carcinoma tumor growth in the lungs, which were required cytotoxic T lymphocytes and NK cells. Thus, these data demonstrated that ECF functioned as a mucosal adjuvant that enhanced the immunotherapeutic effect of immune checkpoint inhibitors against metastatic lung cancer.
Plasmacytoid dendritic cells (pDCs) are known to respond to viral infections. However, the activation of pDCs by bacterial components such as lipopolysaccharides (LPS) has not been well studied. ...Here, we found that pDCs, conventional dendritic cells (cDCs), and B cells express high levels of toll-like receptor 4 (TLR4), a receptor for LPS. Moreover, LPS could effectively bind to not only cDCs but also pDCs and B cells. Intraperitoneal administration of LPS promoted activation of splenic pDCs and cDCs. LPS treatment led to upregulation of interferon regulatory factor 7 (IRF7) and induced production of interferon-alpha (IFN-α) in splenic pDCs. Furthermore, LPS-dependent upregulation of co-stimulatory molecules in pDCs did not require the assistance of other immune cells, such as cDCs. However, the production levels of IFN-α were decreased in cDC-depleted splenocytes, indicating that cDCs may contribute to the enhancement of IFN-α production in pDCs. Finally, we showed that activation of pDCs by LPS requires the TLR4 and myeloid differentiation factor 2 (MD2) signaling pathways. Thus, these results demonstrate that the gram-negative component LPS can directly stimulate pDCs
TLR4/MD2 stimulation in mice.
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.
Developing effective drug delivery systems plays an important role in improving the therapeutic outcomes of anticancer agents. In this study, we investigated the potential of a micellar delivery ...system modified with semi-interpenetrating polymer networks (sIPN) to enhance the therapeutic efficacy of doxorubicin (Dox), a widely used chemotherapeutic agent. The sIPN-modified micelles were prepared by loading polymerizable tetraacrylate moiety into the core of sodium dodecyl benzene sulfonate (SDBS) micelles. To evaluate the stability of SDBS-micelle and SDBS-sIPN, we assessed the stability of the micellar structure under critical micelle temperature conditions. The results demonstrated that incorporating sIPN significantly enhanced the structural stability of the micelles, particularly in response to acrylate unit concentrations, leading to the 60 days continuous release of Dox. Furthermore, we examined the ability of SDBS-micelle-Dox and SDBS-sIPN-Dox to induce apoptosis and necrosis in HeLa cells. Annexin V/PI double staining and flow cytometry analysis revealed that SDBS-sIPN-Dox exhibited a sustained release profile of Dox, resulting in a reduced apoptotic response compared to free Dox and SDBS-micelle-Dox in the given time. These findings highlight the potential of the sIPN-modified micellar delivery system as an efficient drug delivery platform, enabling sustained release and minimizing adverse side effects associated with immediate drug release. The sustained release profile achieved through incorporation of sIPN structures holds great promise for improving the therapeutic outcomes of anticancer agents.
Graphical Abstract
This study involved the fabrication of semi-interpenetrating polymer network (sIPN)-stabilized micelles using an FDAapproved surfactant and loading anti-cancer drug inside. The stability of the resulting stabilized micelle and the prolonged release of the drug, doxorubicin, were evaluated. The findings underscore the potential of sIPN-stabilized micelles as an effective drug delivery platform, capable of providing sustained release and improving therapeutic outcomes for anticancer drugs.
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