AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage. When pathological conditions cause ATP levels to fall, AMPK is activated to restore cellular energy homeostasis[1]. O-304 is a first-in-class, orally available pan-AMPK activator, which increases AMPK activity by suppressing the dephosphorylation of pAMPK. It exhibits a great potential as a drug to treat type 2 diabetes (T2D) and associated cardiovascular complications. Mice fed with a high-fat diet (HFD), denoted DIO mice, were treated by oral gavage with vehicle, O304, Metformin, or O304+Metformin (100 mg/kg/day) each for 8 weeks. O304 and O304+Metformin, but not Metformin, averted the HFD-provoked increase in fasted glucose and plasma insulin levels and inhibited insulin resistance[2]. Postoperative pain mice models made by incision in the left plantar hindpaw were treated by oral gavage with vehicle, metformin 200 mg/kg, O304 200 mg/kg and O304 200 mg/kg plus metformin 200 mg/kg, for 3 days. O304 or metformin increased von Frey thresholds (reduced mechanical hypersensitivity) in plantar incision mice compared to vehicle-treated incision mice[3].
O-304 细胞实验
Cell Line
Concentration
Treated Time
Description
References
mouse primary islets
mouse primary islets
O304 increased p-T172 AMPK levels
JCI Insight. 2018 Jun 21;3(12):e99114.
INS-1 insulinoma cells
INS-1 insulinoma cells
O304 increased p-T172 AMPK levels
JCI Insight. 2018 Jun 21;3(12):e99114.
hepatocytes
hepatocytes
O304 dose-dependently suppressed lipid synthesis
JCI Insight. 2018 Jun 21;3(12):e99114.
Human skeletal myotubes
Human skeletal myotubes
O304 increased 2-DeoxyD-glucose (2-DG) uptake in a dose- and AMPK-dependent manner in the absence of insulin
JCI Insight. 2018 Jun 21;3(12):e99114.
Wi-38 human lung fibroblast cells
Wi-38 human lung fibroblast cells
O304 increased pAMPK, pACC, and ATP/protein ratio in a dose-dependent manner
JCI Insight. 2018 Jun 21;3(12):e99114.
INS-1E cells
INS-1E cells
To evaluate the effect of O304 on insulin secretion under hyperglycemic conditions, results showed that O304 prevented and partly reversed the negative effects of chronic hyperglycemia on glucose-stimulated insulin secretion (GSIS).
Commun Biol. 2023 Aug 25;6(1):877.
C2C12 myotubes
C2C12 myotubes
To assess the uncoupling potential of O304, results showed that O304 dose-dependently increased oxygen consumption rate (OCR), indicating its function as a mitochondrial uncoupler.
Commun Biol. 2023 Aug 25;6(1):877.
mouse hippocampal neurons
mouse hippocampal neurons
Pre-treatment with O304 abrogated the suppression effect of NTRK1 knockdown on the activity of the AMPK/ULK1/FUNDC1 pathway and reversed the inhibitory effect of NTRK1 knockdown on mitophagy.
Cell Death Discov. 2023 Oct 31;9(1):404.
Human aortic smooth muscle cells
Human aortic smooth muscle cells
O304 activated AMPK signaling and prevented VSMC phenotypic switching from the contractile to the synthetic phenotype.
Front Pharmacol. 2024 Nov 29;15:1457817.
CBA x C57Bl/6 F1 hybrid mouse islets
CBA x C57Bl/6 F1 hybrid mouse islets
O304 significantly reduced Aldh1a3 expression under high glucose conditions, alleviating β-cell stress
Sci Rep. 2021 Dec 23;11(1):24410.
O-304 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Diet-induced obese (DIO) mice
Oral gavage
100 mg/kg
Once daily for 8 weeks
O304 and O304+Metformin significantly reduced fasted glucose and plasma insulin levels and prevented insulin resistance
JCI Insight. 2018 Jun 21;3(12):e99114.
Mice
STZ-induced diabetic mice and db/db mice
Formulated in diet
0.25, 0.5, 1.0 mg/g
Continuous treatment
To assess the ameliorative effects of O304 on hyperglycemia and its protective effects on β-cell function. Results showed that O304 significantly improved hyperglycemia by dually promoting muscle glucose effectiveness and preserving β-cell function.
Commun Biol. 2023 Aug 25;6(1):877.
ApoE-deficient male mice
Abdominal aortic aneurysm model
Oral
200 mg/kg
Once every 3 days for 28 days
O304 significantly activated AMPK signaling, increased the proportion of contractile VSMCs, and reduced AAA formation and blood pressure.
Front Pharmacol. 2024 Nov 29;15:1457817.
Mice
Aged mouse model
Oral
0.25 or 0.5 mg/g
Continued for 12 months
O304 prevented and reverted age-associated hyperinsulinemia and insulin resistance, and improved cardiac function and exercise capacity in aged mice.
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