Dunaliella salina Alga Protects against Myocardial Ischemia/Reperfusion Injury by Attenuating TLR4 Signaling.

Myocardial ischemia/reperfusion (I/R) injury is marked by rapid increase in inflammation and not only results in myocardial apoptosis but also compromises the myocardial function. Dunaliella salina (D. salina), a halophilic unicellular microalga, has been used as a provitamin A carotenoid supplement and color additive. Several studies have reported that D. salina extract could attenuate lipopolysaccharides-induced inflammatory effects and regulate the virus-induced inflammatory response in macrophages. However, the effects of D. salina on myocardial I/R injury remain unknown. Therefore, we aimed to investigate the cardioprotection of D. salina extract in rats subjected to myocardial I/R injury that was induced by occlusion of the left anterior descending coronary artery for 1 h followed by 3 h of reperfusion. Compared with the vehicle group, the myocardial infarct size significantly decreased in rats that were pre-treated with D. salina. D. salina significantly attenuated the expressions of TLR4, COX-2 and the activity of STAT1, JAK2, IκB, NF-κB. Furthermore, D. salina significantly inhibited the activation of caspase-3 and the levels of Beclin-1, p62, LC3-I/II. This study is the first to report that the cardioprotective effects of D. salina may mediate anti-inflammatory and anti-apoptotic activities and decrease autophagy through the TLR4-mediated signaling pathway to antagonize myocardial I/R injury.

Lumbrokinase regulates endoplasmic reticulum stress to improve neurological deficits in ischemic stroke.

Ischemic stroke is characterized by the loss of cerebral blood flow, which frequently leads to neurological deficits. Tissue plasminogen activator is the only therapeutic agent approved to treat ischemic stroke but increases the risk of intracranial hemorrhage and mortality. The fibrinogen-depleting agent lumbrokinase has been used to improve myocardial perfusion in symptomatic stable angina and to prevent secondary ischemic stroke. Lumbrokinase is highly fibrin-specific and only active in the presence of fibrin. Therefore, lumbrokinase has a low risk of hemorrhage due to excessive fibrinolysis. In this study, we aimed to clarify the neuroprotection of lumbrokinase in mice subjected to permanent middle cerebral artery occlusion. Lumbrokinase significantly attenuated infarct volume and improved neurological dysfunction. Lumbrokinase dramatically decreased the expressions of the endoplasmic reticulum (ER) transmembrane receptor protein inositol-requiring enzyme-1 (IRE1) and its downstream transcription factor, XBP-1, caspase-12, and NF-κB activity, thereby significantly inhibiting apoptosis and autophagy and decreasing the NLRP3 inflammasome. Our evidence indicates that post-stroke treatment with lumbrokinase protects against ischemic stroke, thereby regulating ER stress through the collective inhibitory effect of the IRE1 signaling pathways to decrease apoptosis, autophagy, and inflammatory responses. We suggest that lumbrokinase is potential as an adjuvant treatment for ischemic stroke.

In situ slow-release recombinant growth differentiation factor 11 exhibits therapeutic efficacy in ischemic stroke.

Systemic growth differentiation factor 11 (GDF11) treatment improves the vasculature in the hippocampus and cortex in mice in recent studies. However, systemic application of recombinant GDF11 (rGDF11) cannot cross the brain blood barrier (BBB). Thus, large doses and long-term administration are required, while systemically applied high-dose rGDF11 is associated with deleterious effects, such as severe cachexia. This study tested whether in situ low dosage rGDF11 (1 µg/kg) protects the brain against ischemic stroke and it investigated the underlying mechanisms. Fibrin glue mixed with rGDF11 was applied to the surgical cortex for the slow release of rGDF11 in mice after permanent middle cerebral artery occlusion (MCAO). In situ rGDF11 improved cerebral infarction and sensorimotor function by upregulating Smad2/3 and downregulating FOXO3 expression. In situ rGDF11 was associated with reductions in protein and lipid oxidation, Wnt5a, iNOS and COX2 expression, at 24 h after injury. In situ rGDF11 protected hippocampal neurons and subventricular neural progenitor cells against MCAO injury, and increased newborn neurogenesis in the peri-infarct cortex. Systematic profiling and qPCR analysis revealed that Pax5, Sox3, Th, and Cdk5rap2, genes associated with neurogenesis, were increased by in situ rGDF11 treatment. In addition, greater numbers of newborn neurons in the peri-infarct cortex were observed with in situ rGDF11 than with systemic application. Our evidence indicates that in situ rGDF11 effectively decreases the extent of damage after ischemic stroke via antioxidative, anti-inflammatory and proneurogenic activities. We suggest that in situ slow-release rGDF11 with fibrin glue is a potential therapeutic approach against ischemic stroke.