Table 3.
Preclinical therapeutics (natural compounds, small molecules, or peptides) targeting the UPR signaling pathway (in vivo).
| Compound | Experimental model | Target disease | Therapeutic activity/target | Indication | References |
|---|---|---|---|---|---|
| Berberine | Male Sprague–Dawley rats | Myocardial ischemia/reperfusion (I/R) injury | Activation of AK2/STAT3 signaling pathway and JAK2/STAT3 signaling pathway, attenuation of ERS-induced apoptosis | Downregulation of the phosphorylation levels of myocardial PERK and eIF2α, expression of ATF4 and CHOP in heart tissues | (Zhao et al., 2016) |
| Bisoprolol | Sprague–Dawley rats | Myocardial ischemia/reperfusion (I/R) injury | Inhibition of UPR signaling pathways, suppression of TNF-α and IL-6 secretion, downregulation of caspase-12 and caspase-3 expressions | Attenuation of UPR signaling pathway, downregulation of PERK/ATF4/eIF2α | (Zhang et al., 2017b) |
| AG1478 and 542 (small-molecule EGFR inhibitors) | C57BL/6 mice | Hyperlipidemia/obesity-induced cardiac injuries | Downregulation of TLR4/c-Src, suppression of TNFα and IL-6 expression | Reduction of cardiac inflammatory injuries | (Li et al., 2016) |
| Adiponectin U0126 (ERK1/2 inhibitor) | Lipotoxicity-induced cardiomyopathy | Inhibition of the caspase-3 and PARP activity, inhibition of ERK1/2 signaling pathway, activation of the Akt signaling pathway | Increase protein level of PI3K/Akt and decrease the protein level of ERK1/2 | (Wei et al., 2012) | |
| Thioredoxin 2 | Wistar rats | Diabetic cardiomyopathy | Diminish high-glucose-induced mitochondrial oxidative damage and improved ATP production | (Li et al., 2017) | |
| D942 (small molecule) and curcumin (combination treatment) | C57BL/6 mice | Myocardial ischemia/reperfusion (I/R) injury | Activation of AMPK pathway or inhibition of mTOR signaling | Upregulates autophagy and promotes cell survival | (Yang et al., 2013) |
| Tauroursodeoxycholic acid (chemical chaperone) | Calreticulin-induced Transgenic mice hearts (Heart CRT+) | Heart failure | Inhibition of IRE1α pathway of the UPR | Prevents cardiac fibrosis and preserve heart function | (Groenendyk et al., 2016) |
| Metformin (AMPK activator) | Diabetic obese mice | Cardiomyopathy | Activation of AMPK-induced PPARδ | Suppresses ER stress and protects endothelial function | (Jung and Choi, 2016) |
| Apelin-13 | —————— | Myocardial ischemia/reperfusion (I/R) injury | Modulation of PERK/CHOP, PI3K/Akt, AMPK and ERK pathways | Inhibits ERS-dependent apoptosis activation via the | (Lee and Ozcan, 2014) |
| Atorvastatin | —————— | Heart failure | GRP78, caspase-12, CHOP | Inhibits ER stress-induced apoptosis | (Liu, M. Q. et al., 2016) |
| Metoprolol and propranolol β-adrenergic receptor (β-AR) blockers | Rats | Hypertrophic failing hearts | Downregulation of GRP78, XBP-1, and calmodulin kinase II (CaMKII), CHOP | Suppression of ERS and ERS-mediated apoptosis | (Liu, M. Q. et al., 2016) |