Ischemic stroke represents a significant danger to human beings, especially the elderly. Interventions are only available to remove the clot, and the mechanism of neuronal death during ischemic stroke is still in debate. Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs. Here we report that the serine protease, thrombin, instigates ferroptotic signaling by promoting arachidonic acid mobilization and subsequent esterification by the ferroptotic gene, acyl-CoA synthetase long-chain family member 4 (ACSL4). An unbiased multi-omics approach identified thrombin and ACSL4 genes/proteins, and their pro-ferroptotic phosphatidylethanolamine lipid products, as prominently altered upon the middle cerebral artery occlusion in rodents. Genetically or pharmacologically inhibiting multiple points in this pathway attenuated outcomes of models of ischemia in vitro and in vivo. Therefore, the thrombin-ACSL4 axis may be a key therapeutic target to ameliorate ferroptotic neuronal injury during ischemic stroke.

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Curcumin has been widely used as a food additive for centuries and has been recently explored for its anti-inflammatory and antitumor properties. Although curcumin is pharmacologically safe and efficacious to certain cancers, its role against acute myeloid leukemia (AML) still remains unclear, and it lacks clinical application due to low water solubility and low in vivo bioavailability. To address these issues, we developed a novel curcumin liposome modified with hyaluronan (HA-Cur-LPs) to specifically deliver curcumin to AML by targeting CD44 on AML cell surface. When compared with free curcumin and nontargeted liposome (Cur-LPs), the HA-Cur-LPs exhibited good stability, high affinity to CD44, increased cellular uptake, and more potent activity on inhibiting AML cell proliferation. The KG-1 cell implanted AML mice had significantly delayed, or even prevented, AML progression following treatment with 50 mg/kg of curcumin dose in the HA-Cur-LPs every 2 days for 2 weeks. Mechanistically, the anti-AML effects of HA-Cur-LPs were achieved by inhibiting Akt/ERK pathways and activating caspase-dependent apoptosis. Moreover, HA-Cur-LPs played a critical role in downregulation of DNMT1 expression in AML, leading to DNA hypomethylation and reactivation of tumor suppressor genes such as miR-223. The development and assessment of the HA-Cur-LPs in this study provide another potential choice for AML therapy, using HA-Cur-LPs as either a single treatment agent or in combination with other treatments.

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Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a very effective surgical procedure for Parkinson’s disease. It significantly improves cardinal parkinsonian symptoms as well as levodopa-induced dyskinesia. Interestingly, STN-DBS can also provoke or exacerbate dyskinesia. In the present study, stimulation-induced dyskinesia (SID) was found in the early stage (less than 1 month) after STN-DBS in some patients. The aim was to discuss this interesting phenomenon. Methods: Side effects of each electrode contact were tested at 9.0 ± 3.8 days (range, 3–16 days) after STN-DBS, and 40 contacts of 16 electrodes (15 patients) were found to induce dyskinesia. The location of these contacts was calculated in the postoperative magnetic resonance imaging, and was compared to the positions of active contacts and dorsal margin of the subthalamic nucleus (STN). Results: Most SID at the threshold manifested as repetitively dystonic involuntary movement, and the most common site was the contralateral lower limb (27/40, 67.5%). The mean location of the 40 contacts with SID was 11.9 ± 0.9 mm lateral, 0.4 ± 1.7 mm anterior, and 1.8 ± 1.9 mm inferior to the midcommissural point. The point was located inferior to the dorsal margin of the STN (p = 0.01, t tests), and no significant difference was found between this point and the location of active contacts (p > 0.05, t tests). Conclusion: In the early stage after STN-DBS, dyskinesia is easily induced by high-frequency stimulation of the upper portion of the STN, which may predict the best site for chronic stimulation.