FOXO3 x STAT3

Hypercholesterolaemia is a prevalent etiological factor of cardiovascular diseases (CVDs). Gastrodin (Gas), the paramount active constituent in Gastrodia elata Bl., has lipid-lowering and anti-inflammatory properties for the treatment of CVDs. Nevertheless, the underlying mechanism responsible for hypolipidemic efficacy remains to be elucidated. The signalling pathwayof PCSK9/LDLR is a key signalling pathway that regulates cholesterol metabolism.

This investigation elucidated whether Gas has an inhibitory effect on hypercholesterolaemia and whether this effect is associated with the regulation of the PCSK9/LDLR signalling pathway.

We induced hypercholesterolaemia of mice by feeding them a high-fat diet (HFD) for 12 weeks to analyse the therapeutic effects and related pathways of Gas in vivo. In vitro, western blotting, qRT-PCR, molecular docking, and transfection were employed to verify the molecular mechanism of action of Gas in the treatment of hypercholesterolaemia.

Gas exhibited potent therapeutic effects against hypercholesterolaemia in HFD mice. Moreover, the HFD-induced hepatic lipid accumulation and liver damage were attenuated by Gas. Mechanistically, Gas decreased the expression of PCSK9 via inhibiting the JAK2/STAT3 signalling pathway to suppress HNF-1α and promote FoxO3a. In addition, Gas increased LDLR transcription via SREBP2 activation.

Collectively, our data provide new insights into the prevention and treatment of hyperlipidaemia by Gas.

This study explored the role and mechanism of action of ginsenoside Rc in treating septic cardiomyopathy. Ginsenoside Rc mitigated LPS-induced oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction in cardiomyocytes and inhibited M1 polarization in macrophages. Ginsenoside Rc reduced the stimulating effect of M1-polarized macrophages on LPS-induced cardiomyocyte injury. Network pharmacological analysis suggested that ginsenoside Rc may play a role in septic cardiomyopathy through modulation of the STAT3/FoxO3a/Sirt1 pathway, which was validated in in vitro experiments. Ginsenoside Rc suppressed the expression of STAT3/FoxO3a pathway proteins and upregulated Sirt1. Moreover, influences of ginsenoside Rc on LPS-induced cardiomyocyte injury and macrophage polarization were abolished by ML115, a STAT3 agonist. In vivo, ginsenoside Rc notably improved myocardial injury and attenuated macrophage activation and inflammation in septic mice. Collectively, Ginsenoside Rc can ameliorate septic cardiomyopathy by modulating the STAT3/FoxO3a/Sirt1 pathway and altering macrophage polarization.

Herba Siegesbeckiae (HS), well-recognized among the commonly used traditional medicines, is popular as one of the in-clinic treatments for rheumatoid arthritis, ischemic stroke, paralysis, asthma, and allergic disorders. However, the underlying mechanisms of neuroprotection and the part played by HS in protection against neuronal apoptosis continue to be nebulous.

This study aims to explore whether HS can alleviate cerebral ischemic injury by protecting neurons and alleviating oxidative stress injury, and to elucidate the molecular mechanisms involved in PI3K/STAT3/FOXO3a signal pathway.

In this study, both in vitro and in vivo experiments were performed to examine the neuroprotective effects of HS on oxidative stress injury and neuronal apoptosis. After the HS treatment, several assays were done to assess the neuroprotection, oxidative stress response, and neuronal apoptosis. Besides, to further clarify the role of HS on the PI3K/STAT3/FOXO3a signal pathway, the effects of combining the HS with an inhibitor, agonist, or siRNA were studied.

From the in vivo and in vitro experiments, it was evident that HS inhibited neuronal apoptosis to a significant degree and offered effective protection against oxidative stress injury by lowering the concentration of the reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH). Moreover, HS obviously up-regulated the principal proteins expression of the PI3K/STAT3/FOXO3a signal pathway, including the PI3K, p-Akt/Akt, and p-FOXO3a/FOXO3a. Additionally, HS reduced the fluorescence intensity of the STAT3 and FOXO3a, and advanced their nuclear translocation both in the in vitro and in vivo models. Nevertheless, after the combined treatment with HS and LY294002, Colivelin or siRNA-FOXO3a, these effects were reversed.

The present study gives pharmacological evidence, revealing that HS wields its protective actions by regulating the PI3K/STAT3/FOXO3a signal pathway, thus inhibiting oxidative stress injury and protecting the neurons from oxidative stress-generated damage. The current study emphasizes the potential of HS as a therapeutic means of treatment of oxidative stress conditions related to ischemic stroke.