Fig 2: High IMPACT appears to ameliorate stress response when tryptophan dioxygenases are upregulated in prostate adenocarcinoma. a) Scatter plots between the expression of IMPACT (y-axis), GCN2 pathway genes (EIF2AK4, ATF4, DDIT3), mTOR pathway genes (MTOR, RPS6KB1) and β-actin within the TCGA prostate adenocarcinoma cohort. P and r indicates statistical significance and correlation coefficient, respectively. Marginal grey lines represent histograms. b) Inter-gene correlations and differential expression of genes from Fig. 2 in prostate adenocarcinoma (left) and non-cancer prostate tissue (right). The two grey scale vertical bars denote mean gene expression value. The middle bar next to the gene names indicates differential expression (Δ) between cancer (C) and non-cancer (N) samples. The heatmap was generated using function corplot2 from the package pcot2 [37] in R; the Manhattan distance metric was used for clustering

Fig 3: Model for a stressed-induced mTORC2 signaling pathway targeting ATF4/Sirt5 in cell survival.mTORC2 senses cellular stresses arising from glutamine deprivation or an acute inhibitionof glutamine metabolism. Upon its phosphorylation by mTORC2, PKC targets Nrf2 which triggers sustained ATF4 and Sirt5 transcription and subsequent protein production to promote cell survival in the face of metabolic and oxidative stress.

Fig 4: GRP78 inhibition suppresses JI017-induced ER stress and cell death in ovarian cancer cells. (A–D) A2780 and OVCAR-3 cells were transfected with GRP78-specific siRNA in the presence or absence of JI017 (300 µg/mL, 24 h), and WST-1, LDH, caspase-3 activity, and intracellular Ca2+ assay were performed; *, p < 0.05. (E) Western blot analysis of GRP78, p-PERK, PERK, p-eIF2α, eIF2α, ATF4, CHOP, and cleaved caspase-3 in JI017 (300 µg/mL, 24 h)-treated A2780 and OVCAR-3 cells in the presence or absence of GRP78 siRNA (30 nM, 24 h). β-actin was used as a protein loading control.

Fig 5: Working model about IL-22 protecting mice against LPS-induced acute liver injury.IL-22 activates autophagy in hepatocytes via stimulating ATF4-ATG7 signaling pathway and protects hepatocytes against LPS-induced apoptosis. Pre-treatment of IL-22 is effective to alleviate LPS-induced acute liver injury.