Irisin Attenuates Apoptosis Following Ischemia-Reperfusion Injury Through Improved Mitochondria Dynamics and ROS Suppression Mediated Through the PI3K/Akt/mTOR Axis.

Irisin is a muscle-derived hormone that promotes the survival of motor neurons and enhances muscle size following injury. In this study, we investigated the beneficial effects and mechanism(s) of action of irisin in response to cerebral ischemia-reperfusion injury (CIRI). Right-middle cerebral artery occlusion (MCAO) and hypoxia/reoxygenation (H/R) models were generated in C57BL/6 J mice. Mouse neuronal cell lines (NSC-34) were used to confirm the molecular mechanisms of the protection afforded by irisin in response to CIRI. We found that irisin (250 µg/kg) improved cerebral function and reduced the cerebral infarct volume following CIRI. Irisin also protected neuronal cells against ischemia-reperfusion (I/R) induced apoptosis, assessed via TUNEL, and cleaved Caspase-3 staining. Western blotting of neuronal tissue from irisin treated I/R mice showed lower expression of pro-apoptotic Bax and caspase-9 (P < 0.001 and P < 0.01) and increased levels of the pro-survival protein Bcl-2 (P < 0.01 & P < 0.001 vs. I/R). Irisin also reduced the levels of reactive oxygen species (ROS) characterized through malondialdehyde (MDA) assays. Irisin was found to maintain mitochondrial homeostasis through the suppression of mitochondrial fission-linked dynamin-related protein 1 in CIRI mice (P < 0.01 and P < 0.05 v. I/R cohort). Moreover, mitochondrial fusion-related protein (Mfn2) and Opa1 expression were rescued following irisin treatment (P < 0.001 and P < 0.01 v. I/R cohort). Cell-based assays showed that irisin activates PI3K/AKT/mTOR signaling in the neurons of CIRI mice. Furthermore, the beneficial effects of irisin on NSC-34 cell-survival, mitochondrial function, and ROS generation were reversed by VS-5584, a highly specific PI3K/AKT/mTOR inhibitor. Collectively, these data highlight the ability of irisin to alleviate CIRI in vivo and in vitro. The mechanisms of action of irisin include the attenuation of apoptosis through the prevention of mitochondrial fission and increased mitochondrial fusion and the alleviation of oxidative stress through activation of the PI3K/AKT/mTOR axis. We therefore identify irisin as a much-needed therapeutic for CIRI.

Rodent models for intravascular ischemic cerebral infarction: a review of influencing factors and method optimization.

Rodent models for cerebral infarction are useful for studying human focal ischemic cerebral infarction, by simulating etiological and pathophysiological mechanisms. However, differences in the selection of anesthetic drugs, surgical methods and other factors may affect the extent to which preclinical models reflect the human condition. This review summarizes these factors. We searched pertinent literature from the MEDLINE and Web of Science databases, and reviewed differences in rodent strain, anesthesia method, sex, surgical method, timing of surgery, and factors influencing postoperative evaluation. In particular, circadian rhythm was found to have a significant impact on the outcome of cerebral infarction in rodent models. This information will enable researchers to quickly and clearly select appropriate modeling methods, acquire reliable quantitative experimental results, and obtain basic data for fundamental mechanism research.

New Diterpenes from Arenga pinnata (Wurmb.) Merr. Fruits.

Three new ent-kauran-type diterpenes (1⁻3), named arenterpenoids A⁻C, and five known ones (4⁻8) were isolated and identified from Arenga pinnata (Wurmb.) Merr. Fruits. The structures of these compounds were established by 1D and 2D NMR spectra and HR-ESI-MS. To the best of our knowledge, this is the first scientific report of diterpenes from Arenga genus.