The American journal of Chinese medicine
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Doxorubicin (DOX) is a most common anthracycline chemotherapeutic agent; however, its clinical efficacy is limited due to its severe and irreversible cardiotoxicity. Ferroptosis, characterized by iron overload and lipid peroxidation, plays a pivotal role in DOX-induced cardiotoxicity. Resveratrol (RSV) displays cardioprotective and anticancer effects, owing to its antioxidative and anti-inflammatory properties. ⋯ Notably, the protective effect of RSV in DOX-mediated ferroptosis was similar to that of Fer-1 in vitro and in vivo. Thus, the p62-NRF2 axis plays a critical role in regulating DOX-induced ferroptosis in cardiomyocytes. RSV as a potent p62 activator has potential as a therapeutic target in preventing DOX-induced cardiotoxicity via ferroptosis modulation.
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Preconditioning has a powerful protective potential against myocardial ischemia-reperfusion injury (I/R). Our prior work demonstrated that baicalein, a flavonoid derived from the root of Scatellaria baicalensis Georgi (also known as Huangqin), confers this preconditioning protection. This study further explored the mechanisms of baicalein preconditioning (BC-PC) in mouse cardiomyocytes. ⋯ In addition, BC-PC decreased phosphorylation of pyruvate dehydrogenase (PDH) reflecting upregulated PDH activity, and increased ATP production at 30 min during reperfusion. Taken together, baicalein preconditioning-induced cardioprotection involves pro-oxidant generation, activates survival signaling Akt/eNOS/NO, and improves metabolic recovery after I/R injury. Our work provides new perspectives on the effect of baicalein on cardiac preconditioning against I/R injury.
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Combining innocuous natural products with cytotoxic agents may enhance the effectiveness of chemotherapy. Tangeretin is a citrus flavonoid that has antineoplastic properties, but its mechanism of action is still unknown. Here, we used a high throughput-screening (HTS) platform to screen for drugs that may synergize with tangeretin and confirmed the top hits against colorectal cancer (CRC) cells in vitro and in vivo. 5-Fluorouracil (5-FU) and PI3K/Akt inhibitors have come out as top hits that show a strong synergy effect with tangeretin by HTS. ⋯ In 5-FU treated cells, tangeretin inhibited miR-21 induction, rescued the expression of the target PTEN, reduced Akt activation, and induced autophagy. Together, our data indicated that a natural product, such as tangeretin, can modulate miR-21 expression and that this pathway might be a potential therapeutic target for CRC. Combining tangeretin with 5-FU may be useful in the clinic, since 5-FU is the current first line drug for treating CRC.
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Our study aimed to explore the function and mechanism of Dexmedetomidine (Dex) in regulating myocardial ischemia/reperfusion (I/R)-induced mitochondrial apoptosis through lncRNA HCP5. We demonstrated Dex suppressed I/R-induced myocardial infarction and mitochondrial apoptosis in vivo. Dex induced the expression of lncRNA HCP5 and MCL1, inhibited miR-29a expression and activated the JAK2/STAT3 signaling. ⋯ Knockdown of miR-29a also alleviated cardiomyocyte apoptosis by upregulating MCL1. Overexpression of lncRNA HCP5 activated the JAK2/STAT3 signaling through sponging miR-29a and enhancing MCL1 expression in cardiomyocytes. Dex mitigated myocardial I/R-induced mitochondrial apoptosis through the lncRNA HCP5/miR-29a/MCL1 axis and activation of the JAK2/STAT3 signaling.
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Tanshinone IIA (TanIIA) has neuroprotective effects against cerebral ischemia reperfusion injury (CIRI), but its clinical application is limited due to poor water solubility and robust first pass elimination property. In this study, we developed microemulsion loaded with TanIIA (TanIIA ME) to break through these limitations, and explored the neuroprotective effect of TanIIA ME against CIRI and the epigenetic regulation mechanism of this neuroprotection. In vivo, middle cerebral artery occlusion (MCAO) models were treated with TanIIA ME and TanIIA solution or sodium valproate as a control. ⋯ Additionally, in OGD/R models, the results demonstrated that TanIIA ME treatment had a better neuroprotective effect along with increased H3K18ac, H4K8ac, and MAP-2 expression and decreased NMDAR1 and caspase-3 expression, compared with the other treatments except sodium valproate. Overall, TanIIA ME treatment exhibited superior efficacy in protecting against CIRI through mechanisms that might involve the inhibition of NMDAR1 and caspase-3 expression and the enhancement of MAP-2 expression by regulating histone H3K18 and H4K8 acetylation. Thus, TanIIA ME could be potentially used to develop a promising drug for the treatment of ischemic stroke.