Expression of SR-BI and LXRα in Macrophage Origin Foam Cells of Mouse RAW264.7 Up-regulated by Astragalus Polysaccharide.

Objective: To investigate the influences of Astragalus polysaccharides (APS) on the expressions of SR-BI(Scavenger receptor-BI) and LXR α in RAW264.7 macrophage origin foam cells. Methods: Mouse RAW264.7 cells were induced in foam cells and identification of the foamed by oil-red O staining. The RAW264.7 macrophage origin foam cells were dealt with APS with distinct contents (0, 10, 20, 50, or 100 mg/L). The mRNA and protein expressions of SR-BI and LXRα were measured by RT-PCR as well as ELISA, respectively. Results: Macrophages were differentiated into foam cells 48 h after ox-LDL induction. In contrast to the control part, the mRNA and protein expressions of SR-BI and LXRα in RAW264.7 macrophage origin foam cells were up-regulated dosage-dependently after being treated with different concentrations of APS (P < 0.05). Conclusion: APS could promote intracellular cholesterol efflux by up-regulating the expressions of SR-BI and LXR α of RAW264.7 cells.

The impaired anti-tumoral effect of immune surveillance cells in the immune microenvironment of gastric cancer.

Immune surveillance cells in the tumor microenvironment play an important role in inhibiting tumorigenesis and metastasis, but their anti-tumoral effects are impaired. The anti-tumoral effects of innate immune cells and adaptive immune cells in the immune microenvironment of gastric cancer are also impaired. Their degree of functional impairment is closely related to the prognosis of gastric cancer. Multiple factors inhibit the anti-tumoral effects of immune surveillance cells, such as decreased numbers of immune surveillance cells, reduced activating receptors, decreased secretion of pro-inflammatory cytokines, increased apoptosis, elevated expression of coinhibitory molecules on cancer cells or immunosuppressive cells, increased secretion of inhibitory cytokines, impaired antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by antigen-presenting cells (APCs) and pro-tumoral polarization of cells with functional plasticity. These factors can potentially combine to suppress the immune surveillance cells' functions. However, there are conflicting conclusions on the effects of immune surveillance cells on gastric cancer cells. These contradictions are partly due to the heterogeneity of the tumor microenvironment.

Relationship among the acute toxicity, critical body residue, and bioconcentration of ortho-dinitrobenzene in zebrafish (Danio rerio) based on toxicokinetics.

The internal critical concentration represented by the critical body residue (CBR) is an ideal indicator for reflecting the toxicity of a chemical. Although some authors have realized that the CBR50 can be calculated from the LC50 via the bioconcentration factor (BCF), the effects of exposure time and exposure concentration on the relationship between the LC50 and CBR50 have not been investigated to date. In this paper, the LC50 and CBR50 of ortho-dinitrobenzene in zebrafish were experimentally determined and their relationship was investigated. The results showed that ortho-dinitrobenzene exhibited excess toxicity and cannot completely be identified as a reactive compound based on toxic ratio. Comparison of the measured CBR50 and the CBR50 calculated from the LC50 via the BCF showed that there was a 0.46 log unit difference. Investigation of the relationship between the concentration in fish calculated by the toxicokinetic model and exposure time showed that the bio-uptake of fish was fast and reached a steady state in the toxicity test, indicating that the difference in CBR50 values could not be attributed to the different exposure times used in toxicity and BCF assays. On the other hand, investigation of the measured bioconcentration ratio (BCR) showed that the BCR (or BCFapp) decreased with increasing exposure concentration. Compared with the CBR50 calculated from the LC50 via the BCF, the CBR50 calculated from the LC50 via the BCFapp is close to the measured CBR50, suggesting that the difference in CBR50 values is attributed to the different exposure concentrations used in the BCF and toxicity assays.

Investigation on the relationship between critical body residue and bioconcentration in zebrafish based on bio-uptake kinetics for five nitro-aromatics.

It is well known that the critical body residue (CBR) can be estimated via bioconcentration factor (BCF). However, the relationship between CBR and BCF in zebrafish has not been carried out based on bio-uptake kinetics for nitro-aromatics. In this paper, the time-variable concentrations and CBRs in zebrafish were determined for five nitro substituted benzenes. The result shows that CBR values can well be calculated from the BCF and external critical concentrations (LC50). Although CBRs measured from 5 h exposure period are greater than the CBRs obtained from 96 h for the five nitro-aromatics, no significant difference was observed, indicating that the CBR approach is a truer measure of chemical levels in exposed organisms and an ideal indicator to reflect the toxicity of a chemical. The bio-uptake can well be described by first-order kinetics and reach steady-state within 48 h. Almost same BCF values are obtained from the ratio of concentration in the fish (Cf) and in the water (Cw) at apparent steady-state and the ratio of the rate constants of uptake (k1) and depuration (k2) assuming first-order kinetics. The toxicity ratio (TR) can reflect the difference of internal critical concentrations and be used to identify mode of action.

Discriminating modes of toxic action in mice using toxicity in BALB/c mouse fibroblast (3T3) cells.

The objective of this study was to determine whether toxicity in mouse fibroblast cells (3T3 cells) could predict toxicity in mice. Synthesized data on toxicity was subjected to regression analysis and it was observed that relationship of toxicities between mice and 3T3 cells was not strong (R2 = 0.41). Inclusion of molecular descriptors (e.g. ionization, pKa) improved the regression to R2 = 0.56, indicating that this relationship is influenced by kinetic processes of chemicals or specific toxic mechanisms associated to the compounds. However, to determine if we were able to discriminate modes of action (MOAs) in mice using the toxicities generated from 3T3 cells, compounds were first classified into "baseline" and "reactive" guided by the toxic ratio (TR) for each compound in mice. Sequence, binomial and recursive partitioning analyses provided strong predictions of MOAs in mice based upon toxicities in 3T3 cells. The correct classification of MOAs based on these methods was 86%. Nearly all the baseline compounds predicted from toxicities in 3T3 cells were identified as baseline compounds from the TR in mice. The incorrect assignment of MOAs for some compounds is hypothesized to be due to experimental uncertainty that exists in toxicity assays for both mice and 3T3 cells. Conversely, lack of assignment can also arise because some reactive compounds have MOAs that are different in mice compared to 3T3 cells. The methods developed here are novel and contribute to efforts to reduce animal numbers in toxicity tests that are used to evaluate risks associated with organic pollutants in the environment.