Kirenol alleviates inflammation and oxidative stress to improve myocardial ischemia/reperfusion injury in rats.

The ischemic heart disease gravely threatens human health and even results in death. Kirenol is predominantly derived from the Herba Siegesbeckiae plant species and possesses a wide range of biological effects (such as antibacterial, anti-inflammatory, anti-cancer and cardioprotective). However, the regulatory effects and associated mechanisms of kirenol in myocardial ischemia/reperfusion injury (MI/RI) remain unclear. In this study, firstly, the MI/RI rat model was established. It was demonstrated that kirenol protected against the aggravation of cardiac function in MI/RI rats. In addition, the inflammation was induced by ischemia reperfusion (IR), which was likewise affected by kirenol (5 or 10 mg/kg). Moreover, IR enhanced oxidative stress, a process that was counteracted by kirenol. Next, cell apoptosis was discovered to be heightened after IR, but this effect was neutralized by kirenol. Finally, it was uncovered that kirenol has the ability to block the activation of the NF-κB pathway. In conclusion, it was disclosed that kirenol alleviated inflammation and oxidative stress through modulating the NF-κB pathway to improve MI/RI in rats. This work may offer novel insights for searching useful drugs for treating MI/RI.

Shi J ，Guan B ，Gong M ，He X ... -  《-》

Targeted Delivery and ROS-Responsive Release of Lutein Nanoassemblies Inhibit Myocardial Ischemia-Reperfusion Injury by Improving Mitochondrial Function.

Myocardial ischemia-reperfusion injury (MI/RI) is associated with increased oxidative damage and mitochondrial dysfunction, resulting in an elevated risk of mortality. MI/RI may be alleviated by protecting cardiomyocytes from oxidative stress. Lutein, which belongs to a class of carotenoids, has proven to be effective in cardiovascular disease treatment due to its remarkable antioxidant properties, but its application is limited due to its poor stability and low bioavailability in vivo. In this study, a delivery system was developed based on distearoyl phosphatidyl ethanolamine (DSPE)-thiol-ketone (TK)-PEG2K (polyethylene glycol 2000) (abbreviated as DTP) and PCM-SH (CWLSEAGPVVTVRALRGTGSW) to deliver lutein (abbreviated as lutein@DTPP) to damaged myocardium. First, lutein, lutein@DTP, or lutein@DTPP were injected through the tail vein once a day for 3 days and then MI/RI model rats were established by exposing rats to ischemia for 45 min and reperfusion for 6 h. We employed a range of experimental techniques including qRT-PCR, Western blotting, transmission electron microscopy, immunohistochemistry, immunofluorescence, flow cytometry, immunoprecipitation, molecular docking, and molecular dynamics simulations. Lutein@DTPP exhibited good myocardial targeting and ROS-responsive release. Our data suggested that lutein@DTPP effectively suppresses ferroptosis in cardiomyocytes. Mechanistically, we observed an upregulation of mouse double minute-2 (MDM2) in the hearts of MI/RI models and cardiomyocytes exposed to hypoxia/reoxygenation (H/R) conditions. In addition, NADH-ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1) translocation from the cytosol to the mitochondria was inhibited by MDM2 upregulation. Notably, no significant variation in the total NDUFS1 expression was observed in H/R-exposed cardiomyocytes following treatment with siMDM2. Further study indicated that lutein facilitates the translocation of NDUFS1 from the cytosol to mitochondria by directly binding and sequestering MDM2, thereby improving mitochondrial function and inhibiting ferroptosis. Lutein@DTPP promoted the mitochondrial translocation of NDUFS1 to restore mitochondrial function and inhibited the ferroptosis of cardiomyocytes by directly binding and sequestering MDM2.

Shi P ，Sha Y ，Wang X ，Yang T ，Wu J ，Zhou J ，Liu K ，Guan X ，Wang S ，Liu Y ，Gao J ，Sun H ，Ban T ，Cao Y ... -  《International Journal of Nanomedicine》

Erratum: Eyestalk Ablation to Increase Ovarian Maturation in Mud Crabs.

《Jove-Journal of Visualized Experiments》

Inhibition of CCR2 attenuates NLRP3-dependent pyroptosis after myocardial ischaemia-reperfusion in rats via the NF-kB pathway.

Myocardial infarction (MI) is a leading cause of mortality worldwide, contributing significantly to long-term cardiac dysfunction and heart failure. Effective therapeutic strategies are urgently needed to mitigate the extensive damage caused by MI and subsequent ischemia-reperfusion (I/R) injury. This study investigates the role of the Chemokine receptor 2 (CCR2) in regulating NLRP3-dependent cardiomyocyte pyroptosis following myocardial ischemia-reperfusion (MIR), elucidating its molecular mechanisms. A myocardial ischemia-reperfusion model was established using 124 Sprague-Dawley rats by ligating the left coronary artery, inducing 30 min of ischemia. Following ischemia, RS504393, a selective CCR2 antagonist, was administered intraperitoneally one hour after reperfusion. To further explore the underlying mechanisms, the NF-κB pathway agonist Phorbol 12-myristate 13-acetate (PMA) was administered 1 h post-MIR. The results showed a marked increase in CCR2 expression in the heart, peaking on the first day of reperfusion. Treatment with RS504393 significantly improved short-term cardiac function and reduced myocardial infarction size, decreased myocardial pyroptosis and suppressed the expression of NLRP3, GSDMD, Caspase-1, IL-1β, and IL-18 through inhibition of the NF-κB signaling pathway. This effect was reversed with the administration of PMA. In summary, the inhibition of CCR2 shows potential in mitigating myocardial injury following MIR by modulating the NF-κB signaling pathway. These findings highlight CCR2 as a promising therapeutic target for myocardial ischemia-reperfusion injury.

Wang Y ，Ge J ，Dou M ，Cheng X ，Chen X ，Ma L ，Xie J ... -  《-》

Loganin attenuates the inflammation, oxidative stress, and apoptosis through the JAK2/STAT3 pathway in cerebral ischemia-reperfusion injury.

Loganin, a monoterpene iridoid glycoside derived from Cornus officinalis Sieb. Et Zucc, has been reported to have anti-inflammatory and antioxidant activity. Nevertheless, the potential role and molecular mechanism of loganin in cerebral ischemia-reperfusion (I/R) injury are not well-understood. The purpose of the study was to explore the functional role of loganin in the inflammation, oxidative stress, and apoptosis in cerebral I/R injury in rats MATERIALS AND METHODS: Following middle cerebral artery occlusion (MCAO), 80 mg/kg of loganin was intragastrically administered for 7 consecutive days. Neuromotor function scores were performed 24 h after the last administration, and the cerebral infarction volume was determined by TTC straining. The expressions of IL-6, IL-1β, and TNF-α in the brain tissues of MCAO rats were detected by ELISA assay. The activities of ROS, SOD, and MDA were measured by ELISA assay as well. Cell apoptosis were was tested by TUNEL straining. Western blot assay was applied for measuring the protein levels RESULTS: We observed that the expressions of IL-6, IL-1β, and TNF-α were amplitude markedly elevated in the rats following MCAO. Treatment with loganin obviously reduced these expressions in the brain tissues of MCAO rats. ELISA assay showed that ROS generation and MDA activity were increased in MCAO group and it was decreased after treatment with loganin. However, loganin increased the SOD activity, which was reduced by MCAO operation. Moreover, loganin promoted neurological function improvement and inhibited cell apoptosis in the rats after MCAO. Mechanically, loganin triggered JAK2/STAT3 phosphorylation in the rats following MCAO, and activation of JAK2/STAT3 pathway rescued the inhibition effects of loganin on the inflammation, oxidative stress, and apoptosis CONCLUSIONS: These results provide evidence that loganin may alleviate the inflammation, oxidative stress, and apoptosis through the JAK2/STAT3 pathway in MCAO rats.

Xi Y ，Hou X ，Huang Y ，Zhou Y ，Chen Y ，Wang Y ，Cheng H ... -  《-》