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. 2020 Dec 3;21(23):9220. doi: 10.3390/ijms21239220

Figure 2.

Figure 2

(A) Downstream effects of mTOR signaling in response to rapamycin and rapalogs. The inhibition of mTORC1 results in the decrease of the inflammatory response and promotion of apoptosis through regulation of IκB kinase. ULK1 is also inhibited, promoting autophagy. Furthermore, the activity of the eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and S6K1 proteins is decreased, which results in diminished cell growth, proliferation, and protein translation. The inhibition of mTORC1 also decreases p53-mediated gene expression. Moreover, through the inhibition of S6K1, Akt activity is upregulated, generating a feedback loop to the products of decreased mTORC1 activity, specifically via the inhibition of TSC1/2 and GSK-3β. IRS-1: insulin receptor substrate 1; CCL-2: C-C motif chemokine ligand 2, BCL-2: B-cell lymphoma 2; BCL-XL: B-cell lymphoma-extra-large. (B) Downstream effects of mTOR, AMPK, and SIRT1 signaling in response to metformin and resveratrol. Metformin exposure decreases mitochondrial function, increasing the AMP/ATP ratio and NAD+ levels. The increased AMP/ATP ratio activates AMPK, which, in turn, decreases protein translation, cell growth/proliferation, and stimulates autophagy and apoptosis. AMP also activates the nuclear factor erythroid 2-related factor 2 (NRF2), which triggers the synthesis of genes involved in the antioxidant response (ARE). Through inhibition by phosphorylation of the mitogen-activated protein kinase (MAPK1) and CCAAT-enhancer-binding homologous protein, AMPK inhibits and activates the c-Jun N-terminal kinase (which is involved in inflammation, JNK). Furthermore, AMPK also reduces the inflammatory response through the inhibition of the signal transducer and activator of transcription (STAT3). In the presence of resveratrol, the most potent inducer of SIRT1, inflammatory proteins are decreased by the inhibition of NF-κB. Finally, AMPK is also activated by phosphorylation of the liver kinase B1 (LKB1) and deacetylation of SIRT1, creating a feedback loop. Created with BioRender.com.