The structure-activity relationship (SAR) between toxicity and the types of linking ketones of C7 bridged monocarbonyl curcumin analogs (MCAs) was not clear yet. In the pursuit of effective and less ...cytotoxic chemotherapeutics, we conducted a SAR analysis using various diketene skeletons of C7-bridged MCAs, synthesized cyclic C7-bridged MCAs containing the identified low-toxicity cyclopentanone scaffold and an
-methoxy phenyl group, and assessed their anti-gastric cancer activity and safety profile. Most compounds exhibited potent cytotoxic activities against gastric cancer cells. We developed a quantitative structure-activity relationship model (
> 0.82) by random Forest method, providing important information for optimizing structure. An optimized compound 2 exhibited
and
anti-gastric cancer activity partly through inhibiting the AKT and STAT3 pathways, and displayed a favorable
safety profile. In summary, this paper provided a promising class of MCAs and a potential compound for the development of chemotherapeutic drugs.
Due to numerous side effects of traditional treatments for toxoplasmosis, it is urgent to develop new anti-Toxoplasma agents with high efficiency and low toxicity. In this study, using ...drug-food-homologous chalcone skeleton as a leading compound, 6 series of chalcone derivatives were designed, synthesized, and almost 1/2 compounds have good anti-Toxoplasma activity in vitro. The quantitative structure-activity relationship model of the anti-Toxoplasma activity of the second batch of compounds was established by random forest method (R2 = 0.9407). The Michael receptor in the molecular skeleton of chalcones plays an important role in improving the activity. Among these compounds, four chalcone derivatives exhibited potent anti-T. gondii activity and low cytotoxicity in vitro. Specifically, three of them (4a, 4c and 5e) effectively inhibited the proliferation of Toxoplasma tachyzoites in vivo. Liver and spleen index and biochemical parameters, such as alanine aminotransferase, aspartate aminotransferase and malondialdehyde were significantly decreased by the three chalcone derivatives, suggesting that they have protective effects on the liver of mice infected with Toxoplasma tachyzoites. Overall, this article provides a series of promising compounds for the development of anti-Toxoplasma agents.
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•Novel chalcone derivatives 4a, 4c and 5e showed potent anti-Toxoplasma gondii effects at low concentration with low cytotoxicity in vitro and in vivo.•The anti-T. gondii activity and liver-protective effects of 4a, 4c and 5e were comprehensively evaluated by biochemical parameters.•Novel chalcone derivatives 4a, 4c and 5e are promising for the treatment of toxoplasmosis.
The effects of local myocardial administration of lactic acid and low-dose edaravone were investigated to determine if this combination provides benefits similar to mechanical postconditioning. We ...randomly divided 108 rats into 6 groups: sham, reperfusion injury, postconditioning (Post), lactic acid (Lac), low-dose edaravone (Eda), and lactic acid + low-dose edaravone (Lac+Eda). The left coronary arteries of the rats were occluded for 45 minutes, before the administration of the treatments. The rats were euthanized at different time points to examine the infarct size and serum markers of myocardial injury and apoptosis and measure the expression of signal pathway markers. We found that the infarct areas caused by ischemic-reperfusion injury were reduced largely by postconditioning and Lac+Eda injection; a similar trend was observed for serum markers of myocardial injury, apoptosis, and hemodynamic parameters. Compared with the Post group, the Lac+Eda group had similar blood pH values, levels of reactive oxygen species, mitochondrial absorbance, and levels of signal pathway marker. The Lac and Eda groups partly mimicked the protective role. These data suggest that local myocardial administration of lactic acid and low dose of edaravone initiates protective signal pathways of mechanical postconditioning and replicates the myocardial protection.
The aim of the present study was to investigate whether a gradually increasing reperfusion algorithm, in which the brief reperfusion was lengthened as the duration of each reperfusion/reocclusion ...cycle remained fixed, enhances cardioprotection. Rats were randomized into 5 groups: the sham, reperfusion injury (R/I), gradually decreased reperfusion (GDR; 30/10‑25/15‑15/25‑10/30 sec of reperfusion/reocclusion), equal reperfusion (ER; 4 20/20‑sec reperfusion/reocclusion cycles) and gradually increased reperfusion (GIR; 10/30‑15/25‑25/15‑30/10 sec of reperfusion/reocclusion). The rats were sacrificed to measure serum markers, apoptotic indices and infarct size. Western blot analyses were used to analyze the expression of molecules involved in important signaling pathways. All the three postconditioning patterns were found to provide cardioprotection (P<0.05 compared with the R/I group). GIR provided optimum cardioprotection, followed by ER and then GDR. Apoptotic index and serum marker levels were significantly reduced in the GIR compared with the ER group (P<0.05). The enhanced cardioprotection provided by GIR was accompanied by significantly increased levels of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and Bcl‑2, as well as lower levels of p38/c‑Jun N‑terminal kinase (JNK) phosphorylation, tumor necrosis factor α (TNFα), caspase‑8, Bax, caspase‑9 and cytochrome c (Cyt‑c) in the cytoplasm of rats (P<0.05, all compared with ER). The infarct size in the rats of the GIR group was also smaller compared with that in the rats of the ER group, but this difference was not significant (16.30±5.22 vs. 20.57±6.32%, P>0.05). All the variables measured in the present study were significantly improved in the GIR group compared with the GDR group (P<0.05). In conclusion, the association between brief reperfusion and reocclusion is an important factor in postconditioning algorithms. Additionally, GIR results in improved cardioprotection compared with that achieved by the remaining algorithms examined.
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