Del-1 enhances therapeutic efficacy of bacterial cancer immunotherapy by blocking recruitment of tumor-infiltrating neutrophils.

BACKGROUND: Bacterial-mediated cancer immunotherapy (BCI) elicits a more robust initial immune response than conventional immunotherapy, but does not prevent tumor recurrence and metastasis. BCI is associated with recruitment of tumor-infiltrating neutrophils, which could suppress the therapeutic efficacy of this modality. Development endothelial locus 1 (Del-1), a potent inhibitor of neutrophil recruitment, antagonizes lymphocyte function-associated antigen-1 on the vascular endothelium. Here, we aimed to determine the effect of Del-1-secreting S.t△ppGpp on anti-tumor activity and tumor-infiltrating neutrophil recruitment in a mouse model of colon cancer. METHODS: We investigated the anti-cancer activity of Del-1-secreting engineered Salmonella (△ppGpp S. Typhimurium) in the mice colon cancer models. RESULTS: In the present study, we identified that Del-1-secreting engineered Salmonella had more potent anti-cancer activity compared with normal S.t△ppGpp without Del-1 secretion. We postulated that Del-1 expression increased M1 macrophage recruitment to tumors by decreasing tumor-infiltrating neutrophils. This approach could enhance the anti-cancer effects of S.t△ppGpp. CONCLUSIONS: Collectively, the approach of using engineered bacteria that deliver Del-1 to block tumor-infiltrating neutrophil recruitment is a potential therapeutic approach.

Chinese herbal medicine for miscarriage affects decidual micro-environment and fetal growth.

INTRODUCTION: Intrauterine growth restriction complicates 5-10% of pregnancies. This study aims to test the hypothesis that Chinese herbal formula, JLFC01, affects pregnancy and fetal development by modulating the pro-inflammatory decidual micro-environment. METHODS: Human decidua from gestational age-matched elective terminations or incomplete/missed abortion was immunostained using anti-CD68 + anti-CD86 or anti-CD163 antibodies. qRT-PCR and Luminex assay measured the effects of JLFC01 on IL-1ß- or TNF-α-induced cytokine expression in first trimester decidual cells and on an established spontaneous abortion/intrauterine growth restriction (SA/IUGR)-prone mouse placentae. The effect of JLFC01 on human endometrial endothelial cell angiogenesis was evaluated by average area, length and numbers of branching points of tube formation. Food intake, litter size, fetal weight, placental weight and resorption rate were recorded in SA/IUGR-prone mouse treated with JLFC01. qRT-PCR, Western blot and immunohistochemistry assessed the expression of mouse placental IGF-I and IGF-IR. RESULTS: In spontaneous abortion, numbers of decidual macrophages expressing CD86 and CD163 are increased and decreased, respectively. JLFC01 reduces IL-1ß- or TNF-α-induced GM-CSF, M-CSF, C-C motif ligand 2 (CCL2), interferon-γ-inducible protein-10 (IP-10), CCL5 and IL-8 production in first trimester decidual cells. JLFC01 suppresses the activity of IL-1ß- or TNF-α-treated first trimester decidual cells in enhancing macrophage-inhibited angiogenesis. In SA/IUGR-prone mice, JLFC01 increases maternal food intake, litter size, fetal and placental weight, and reduces fetal resorption rate. JLFC01 induces IGF-I and IGF-IR expression and inhibits M-CSF, CCL2, CCL5, CCL11, CCL3 and G-CSF expression in the placentae. DISCUSSION: JLFC01 improves gestation by inhibiting decidual inflammation, enhancing angiogenesis and promoting fetal growth.

Lysosomes involved in the cellular toxicity of nano-alumina: combined effects of particle size and chemical composition.

Nowadays, manufactured nano-particles of aluminum oxide (nano-alumina) have been widely used in many fields with the rapidly developed nano-technology, but their basic toxic data are scarce. It is believed that the smaller nano-particles are able to easily cross the bio-membrane and quickly reach cellular compartments rather than micro-size particles, thus showing more toxic effects. The aim of this study was to compare the toxicity of nano- and micro- particles of alumina for detecting particle size related toxicity, and to compare the toxicity of nano-alumina and nano-carbon with the same particle size for determining chemical composition related toxicity. The present study revealed that nano-particles of alumina were much toxic than micro-alumina particles, indicating a particle size related toxicity; and were much more toxic than nano-carbon particles as well, manifesting a chemical related toxicity. The mechanism might be concerned with the involvement of the lysosomes. In conclusion, toxicity of nano-alumina is a combination of the toxic effects of its particle size and chemical composition.