Pathological experiments should be considered following oral administration of ZnO. Effect of different doses of ZnO nanoparticle on LDH in oral method showed significant differences in control group (p<0.05) at high dose. Levels of IgG, TNF-α and IL-6 also elevated after administration of ZnO. The level of GSH decreased significantly. Lung damages included hyperemia and bleeding, atelectasis, light emphysema, pribronchiolitis, perivasculitis of lymphocyte in intensive level, pneumonia and increased secretion of exudates into bronchial. There was a significant difference in perivasculitis and pribronchiolitis among different doses of ZnO as compared with the control group (p<0.05). The result of this study showed that increasing doses of nanoparticles could cause significant damages to the lung tissue and to increase LDH, IgG, TNF-α and IL-6 and emphasizes that exposure to high concentration of ZnO could cause irreversible damages to different organs including lung and threaten the human health. This finding could be important as a health hazard to those who are in continuous exposure to ZnO nanoparticles.

Cell culture process optimization is a critical solution to most of the challenges faced by the pharmaceutical manufacturing. One of the major problems encountered in large-scale production of therapeutic proteins is misfolded protein production. The accumulation of misfolded therapeutic proteins is an immunogenic signal and a risk factor for immunogenicity of the final product. The aim of this study was the statistical optimization of three-phasic temperature shift and timing for enhanced production of correctly folded Fc-fusion protein. The effect of culture temperatures were investigated using the biphasic culture system. Box–Behnken design was then used to compute temperature and time of shifting optimum. Response surface methodology revealed that maximum production with low level of misfolded protein was achieved at two-step temperature shift from 37°C to 30°C during the late logarithmic phase and 30°C to 28°C in the mid-stationary phase. The optimized condition gave the best results of 1860 mg L−1 protein titer with 24.5% misfolding level. The validation experiments were carried out under optimal conditions with three replicates and the protein misfolding level was decreased by two times while productivity increased by ~ 1.3-fold. Large-scale production in 250 L bioreactor under the optimum conditions was also verified the effectiveness and the accuracy of the model. The results showed that by utilizing two-step temperature shift, productivity and the quality of target protein have been improved simultaneously. This model could be successfully applied to other products.

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