Chronic nonalcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to liver fibrosis, a condition with limited therapy options. Adiponectin is an adipocytokine that regulates glucose and lipid metabolism via binding to its receptors AdipoR1 and AdipoR2, and AdipoRs signaling is reported to enhance fatty acid oxidation and glucose uptake. Here, we synthesize and report an adiponectin-based agonist JT003, which potently improves insulin resistance in high fat diet induced NASH mice and suppresses hepatic stellate cells (HSCs) activation in CCl4 induced liver fibrosis. Mechanistic studies indicate that JT003 simultaneously stimulates AdipoR1- and AdipoR2- mediated signaling pathways as well as the PI3K-Akt pathway. Moreover, JT003 treatment significantly improves ER-mitochondrial axis function, which contributes to the reduced HSCs activation. Thus, the AdipoR1/AdipoR2 dual agonist improves both NASH and fibrosis in mice models, which provides the pharmacological and biological foundation for developing AdipoRs-based therapeutic agents on liver fibrosis.
Metformin is a widely used antidiabetic drug for cancer prevention and treatment. However, the overproduction of lactic acid and its inefficiency in cancer therapy limit its application. Here, we demonstrate the synergistic effects of the lactate/GPR81 blockade (3-hydroxy-butyrate, 3-OBA) and metformin on inhibiting cancer cells growth in vitro. Simultaneously, this combination could inhibit glycolysis and OXPHOS metabolism, as well as inhibiting tumor growth and reducing serum lactate levels in tumor-bearing mice. Interestingly, we observed that this combination could enhance the functions of Jurkat cells in vitro and CD8+ T cells in vivo. In addition, considering that 3-OBA could recover the inhibitory effects of metformin on PD-1 expression, we further determined the dual blockade effects of PD-1/PD-L1 and lactate/GPR81 on the antitumor activity of metformin. Our results suggested that this dual blockade strategy could remarkably enhance the anti-tumor effects of metformin, or even lead to tumor regression. In conclusion, our study has proposed a novel and robust strategy for a future application of metformin in cancer treatment.
Liver fibrosis is the undesirable result of excessive
deposition
of the extracellular matrix (ECM), and elastin is known as one of
the key ECM components. Under specific pathological conditions, elastin
undergoes degradation to produce elastin-derived peptides (EDPs),
which bind to elastin-binding protein (EBP) to activate corresponding
signal pathways, thus accelerating fibrosis progression. Herein, we
describe the discovery of novel cyclic peptides that function as potent
and stable inhibitors to interfere with the peptide–protein
interaction between EDPs and EBP. Remarkably, C
XJ
-2 exhibited potent activities to inhibit
the PI3K/ERK pathway and decrease hepatic stellate cell proliferation
and migration. The subsequent in vivo study demonstrated that C
XJ
-2 possessed potent
antifibrotic efficacy in ameliorating CCl4-induced liver
fibrosis. This work provides a successful pharmacological strategy
for the development of novel inhibitors of EDPs–EBP interaction,
which sheds new light on how cyclic peptides disrupt peptide–protein
interaction and may also provide new structure-oriented therapeutic
candidates in liver fibrosis.
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