ABSTRACT
Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and immunologically "cold" tumors severely compromise its immunotherapeutic outcomes. As such, the reversal of the immunosuppressive tumor microenvironment (TME) has been the premise for improving the effectiveness of AA-based immunotherapy, which hinges upon advanced AA delivery and amplified immune-activating strategies. Herein, a novel Escherichia coli (E. coli) outer membrane vesicle (OMV)-red blood cell (RBC) hybrid membrane (ERm)-camouflaged immunomodulatory nanoturret is meticulously designed based on gating of an AA-immobilized metal-organic framework (MOF) onto bortezomib (BTZ)-loaded magnesium-doped mesoporous silica (MMS) nanovehicles, which can realize immune landscape remodeling by chemotherapy-assisted ascorbate-mediated immunotherapy (CAMIT). Once reaching the acidic TME, the acidity-sensitive MOF gatekeeper and MMS core within the nanoturret undergo stepwise degradation, allowing for tumor-selective sequential release of AA and BTZ. The released BTZ can evoke robust immunogenic cell death (ICD), synergistically promote dendritic cell (DC) maturation in combination with OMV, and ultimately increase T cell tumor infiltration together with Mg2+. The army of T cells is further activated by AA, exhibiting remarkable antitumor and antimetastasis performance. Moreover, the CD8-deficient mice model discloses the T cell-dependent immune mechanism of the AA-based CAMIT strategy. In addition to providing a multifunctional biomimetic hybrid nanovehicle, this study is also anticipated to establish a new immunomodulatory fortification strategy based on the multicomponent-driven nanoturret for highly efficient T cell-activation-enhanced synergistic AA immunotherapy.
Subject(s)
Antineoplastic Agents , Ascorbic Acid , Metal-Organic Frameworks , T-Lymphocytes , Animals , Mice , Metal-Organic Frameworks/chemistry , Ascorbic Acid/chemistry , Ascorbic Acid/pharmacology , T-Lymphocytes/immunology , T-Lymphocytes/drug effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Immunotherapy , Bortezomib/chemistry , Bortezomib/pharmacology , Bortezomib/therapeutic use , Biomimetic Materials/chemistry , Biomimetic Materials/pharmacology , Escherichia coli/drug effects , Silicon Dioxide/chemistry , Immunologic Factors/chemistry , Immunologic Factors/pharmacology , Magnesium/chemistry , Nanoparticles/chemistry , Humans , Cell Line, Tumor , Tumor Microenvironment/drug effects , Drug LiberationABSTRACT
To study the toxic mechanisms of lead (Pb) in plants, the effects of Pb on the morphology and structure of the nucleolus in root tip meristematic cells of Allium cepa var. agrogarum L. were investigated. Fluorescence labeling, silver-stained indirect immunofluorescent microscopy and western blotting were used. Fluorescence labeling showed that Pb ions were localized in the meristematic cells and the uptake and accumulation of Pb increased with treatment time. At low concentrations of Pb (1-10 µM) there were persistent nucleoli in some cells during mitosis, and at high concentration (100 µM) many of the nucleolar organizing regions were localized on sticky chromosomes in metaphase and anaphase cells. Pb induced the release of particles containing argyrophilic proteins to be released from the nucleus into the cytoplasm. These proteins contained nucleophosmin and nucleolin. Pb also caused the extrusion of fibrillarin from the nucleus into the cytoplasm. Western blotting demonstrated the increased expression of these three major nucleolar proteins under Pb stress.
Subject(s)
Cell Nucleolus/drug effects , Lead/toxicity , Onions/growth & development , Cell Nucleolus/chemistry , Meristem/chemistry , Meristem/cytology , Meristem/drug effects , Microscopy, Confocal , Mitosis/drug effects , Nucleoproteins/chemistry , Nucleoproteins/metabolism , Onions/drug effects , Plant Proteins/chemistry , Plant Proteins/metabolism , Plant Roots/cytology , Time FactorsABSTRACT
OBJECTIVE: To evaluate the change in protein expression of peroxiredoxin I (Prx I) during pulmonary fibrosis among rats exposed to silica dust and to investigate the role of Prx I in pulmonary fibrosis. METHODS: Ninety male Wistar rats were randomly divided into control group (n = 60) and experimental group (n = 30). The control group received intratracheal perfusion of saline (1 ml), while the experimental group received intratracheal perfusion of suspension of silica dust (50 mg/ml) to establish a rat model of silicosis. At 1, 2, 3, 4, 6, or 8 weeks after treatment, 10 rats in control group and 5 rats in experimental group were sacrificed. The lung tissues were collected for conventional pathological observation. The protein expression of Prx I at each time point was measured by immunohistochemistry and Western blot. RESULTS: Among the rats exposed to silica dust, Prx I was seen in the form of brown particles that were mainly distributed in the alveolar septa and the cytoplasm of alveolar epithelial cells, macrophages, vascular endothelial cells, and smooth muscle cells around the blood vessels and tracheae. The control group showed weak protein expression of Prx I, and the experimental group had significantly higher protein expression of Prx I than the control group at all time points (P < 0.05). In the experimental group, the protein expression of Prx I was upregulated significantly at 1 and 2 weeks and decreased at 3â¼8 weeks. CONCLUSION: The change in protein expression of Prx I may be one of the important causes of the onset and development of pulmonary fibrosis in rats exposed to free silica.
