5d, a novel analogue of the racemic 3-n-butylphthalide (NBP), has been reported for its free radical scavenging activity in vitro and preventive neuroprotection in vivo. Nevertheless, the mechanism by which 5d attenuated ischemia/reperfusion (I/R) injury is still unknown. Our results showed that 5d significantly increased CK2 activity as well as CK2α and 2α' protein levels after I/R injury. Besides, 5d suppressed the translocation of cytosolic p47phox and Rac1 to the membrane, decreased NOX4 expression and ROS generation. Furthermore, 5d blocked the dissociation between CK2α and Rac1 so as to decrease NADPH oxidase activity. Based on these findings, we propose that the neuroprotective effect of 5d is due to an increase of CK2 activity, which blocks I/R-induced dissociation between CK2α and Rac1, decreases NADPH oxidase activity, inhibits ROS production and finally realizes the neuroprotection of I/R. These findings point to that 5d might be considered an attractive candidate for further studies in ischemic stroke.
Abstract Tetracycline (TET) is a broad-spectrum antibiotic commonly used in the treatment of animals. TET residues in food inevitably threaten human health. High-performance analytical techniques for TET detection are required in food quality assessment. The objective of this study was to establish a label-free fluorescent biosensor for TET detection using specific aptamer-templated silver nanoclusters (AgNCs). An aptamer with a high specific binding ability to TET was used to synthesize a novel DNA-templated AgNCs (DNA-AgNCs). When TET is present, the aptamer’s conformation switched from an antiparallel G-quadruplex to a hairpin structure, altering the connection between AgNCs and the aptamer. Following the transformation of AgNCs into large sized silver nanoparticles (AgNPs), a fluorescence decrease was detected. When used to detect TET in milk, the proposed biosensor displayed high sensitivity and selectivity, with a limit of detection of 11.46 ng/mL, a linear range of 20 ng/mL−10 g/mL, and good recoveries of 97.7–114.6% under optimized conditions. These results demonstrate that the proposed biosensor was successfully used to determine TET quantitatively in food samples, suggesting that our method provides an efficient and novel reference for detecting antibiotics in food while expanding the application of DNA-AgNCs in related fields.
ZJM-289 is a potent racemic agent which inhibits both platelet aggregation and thrombosis superior to a known anti-ischemic stroke drug 3-n-butylphthalide (NBP). Herein, the enantiomers of ZJM-289, (S)-ZJM-289 and (R)-ZJM-289, were synthesized and evaluated for their biological activities. It was observed that the two enantiomers appeared to be almost as effective as ZJM-289 in inhibiting platelet aggregation in vitro and thrombus formation in vivo. Moreover, like ZJM-289, its enantiomers could regulate the ratio of thromboxane B(2) (TXB(2)) and 6-keto-prostaglandin F(1α), and enhanced levels of nitric oxide (NO), cAMP and cGMP, suggesting that the anti-platelet and antithrombotic activities of the enantiomers and ZJM-289 are associated with both the arachidonic acid cascade and cGMP-NO signal pathway. Furthermore, it was found that oral administration of the enantiomers and ZJM-289 for three days significantly reduced the infarct size, brain water content and neurological deficit in rats after cerebral ischemia reperfusion. Importantly, the two enantiomers equally improved blood flow in the ischemic stroke model and modulated endothelial function through releasing moderate levels of NO, which might, at least partially, contribute to their neuroprotection. Collectively, the present study demonstrates that the two enantiomers are as potent as ZJM-289 in inhibition of platelet aggregation and thrombosis and in neuroprotection, and (S)-ZJM-289 shows somewhat better effects than (R)-ZJM-289 and ZJM-289 in a few cases. These findings may provide new insights into the development of therapeutic agents like ZJM-289 for the intervention of thrombosis-related ischemic stroke.
Objective
To explore the effects of two routes of melatonin (MT) administration including intraperitoneal and caudal vein injection on the behavior, histopathology and the expression of myelin basic protein (MBP) and active caspase-3 protein in focal cerebral ischemic rats.
Methods
84 male Sprangue-Dawley rats were randomly divided into normal control group(CON, n=12), middle cerebral artery occlusion group(MCAO, n=24), MT-intraperitoneal group (n=24) and MT-intravenous injection group (n=24) by random number table. Twenty-four hours after ischemia reperfusion (IR), Morris water maze was used to observe the effects of two routes of MT administration on behavior in focal cerebral ischemic rats. 7 d after IR, MBP immunohistochemical and hematoxylin eosin (HE) staining were used to examine the expression of MBP in striatum and histopathological changes in hippocampal CA1 region. 24 h, 72 h and 7 d after IR, the expression of active caspase-3 in hippocampal CA1 region was observed by immunohistochemical staining.
Results
The average escape latencies in Morris water maze in MT-intravenous injection group at different time points were all lower than those of the MT-intraperitoneal, and they were all lower than those of the MCAO group. Swimming time percentage of target quadrant in MT-intravenous injection group were higher than those of the MT-intraperitoneal, and they were all higher than those of the MCAO group (all P<0.01); 7 d after IR, the results of HE staining showed that the hippocampus cells in MCAO group were disarranged with hyperchromatic nucleus and cytoplasm. More hippocampal cells were observed in MT-intraperitoneal and MT-intravenous injection groups, and they were relatively well arranged. The optical density (OD) of MBP in MT-intravenous injection group (105.60±4.04) was significantly higher than those in MCAO group (95.60±2.07) and MT-intraperitoneal injection group (98.00±4.18) (both P<0.01). Immunohistochemical results showed that the number of active caspase-3 positive cells in MT-intravenous injection group ((116.93±12.58)/mm2, (130.16±21.22)/mm2, (88.25±7.80)/mm2) at each time point were significantly lower than those in MT-intraperitoneal injection group ((156.64±32.54)/mm2, (176.49±17.44)/mm2, (127.96±16.73)/mm2)(all P<0.05). At the time points of 24 h and 72 h after IR, there were less active caspase-3 positive cells in MT-intraperitoneal and MT-intravenous injection group compared with those in MCAO group((273.56±32.54)/mm2, (288.63±35.17)/mm2)(all P<0.01).
Conclusion
MT administration by both intraperitoneal and intravenous injection can significantly improve the behavior and attenuate the histopathology and white matter damage, and reduce the cell apoptosis in hippocampal CA1 region in focal cerebral ischemic rats, and the therapeutic effects of MT-intravenous injection are better than MT-intraperitoneal injection.
Key words:
Morris water maze; Brain ischemia; Melatonin; Active caspase-3; Myelin basic protein(MBP); Rat
Time-dependent diffusion magnetic resonance imaging (TDDMRI) is useful for non-invasive characterization of tissue microstructure. The TDDMRI models require both densely sampled q-space (b-value and diffusion direction) and t-space (diffusion time) data for microstructural fitting, leading to very time-consuming acquisition protocols. In this work, we presented a tDKI-Net to estimate diffusion kurtosis at multiple diffusion times, which was fed into the Karger model to obtain K0 and transmembrane exchange time, using downsampled q-space and t-space data. We tested the proposed network in the normal rat brains, as well as those in a rat model of Middle Cerebral Artery Occlusion.
Transcytolemal water exchange can be estimated using diffusion-time-dependent diffusion kurtosis imaging acquired at long diffusion times. However, dMRI signals acquired at long diffusion times using STEAM sequences are typically noisy, and fitting of the nonlinear kurtosis model and the Kärger model accumulates fitting errors. Here, we proposed a Bayesian method for estimating transcytolemal exchange time from the Kärger model and compared accuracy and robustness with conventional least square fitting method in both simulated data and rat brain data in a model of transient middle cerebral artery occlusion. Results indicated improved fitting accuracy and robustness against noise using the Bayesian approach.
Transcranial direct current stimulation (tDCS) recently was shown to benefit rehabilitation of patients with disorders of consciousness (DOC). However, high-Definition tDCS (HD-tDCS) has not been applied in DOC. In this study, we tried to use HD-tDCS protocol (2 mA, 20 min, the precuneus, sustaining 14 days ) to rehabilitate 11 DOC patients. Electroencephalography (EEG) and Coma Recovery Scale–Revised (CRS-R) scores were recorded at before (T0), after a single session (T1), after 7 days' (T2) and 14 days' HD-tDCS (T3) to assess the modulation effects. EEG coherence was measured to evaluate functional connectivity during the experiment. It showed that 9 patients' scores increased compared with the baseline. The central-parietal coherence significantly decreased at the delta band in DOC patients. EEG coherence might be useful for assessing the effect of HD-tDCS in DOC patients. Long-lasting HD-tDCS over the precuneus is promising for the treatment of DOC patients.
To describe the epidemiology of congenital malformations of the external ear (CMEE). Data were obtained from the Birth Defects Surveillance System in Hunan Province, China, 2016 to 2020. The prevalence of CMEEs is defined as the number of cases per 1000 fetuses (births and deaths at 28 weeks of gestation and beyond) (unit: ‰). Prevalence and 95% confidence intervals (CI) were calculated by the log-binomial method. Chi-square trend tests (χ2trend) were used to determine trends in prevalence by year. P < .05 was considered statistically significant. Crude odds ratios (ORs) were calculated to examine the association of sex, residence, and maternal age with CMEEs. Our study included 847,755 fetuses, and 14,459 birth defects were identified, including 1227 CMEEs (accounted for 8.49% of birth defects). The prevalences of birth defects and CMEEs were 17.06‰ (95%CI: 16.78-17.33) and 1.45‰ (95%CI: 1.37-1.53), respectively. A total of 185 microtia-anotias were identified, accounting for 15.08% of CMEEs, with a prevalence of 0.22‰ (95%CI: 0.19-0.25). And 1042 other CMEEs were identified, accounting for 84.92% of CMEEs. From 2016 to 2020, the prevalences of birth defects were 18.20‰, 18.00‰, 16.31‰, 16.03‰, and 16.47‰, respectively, showing a downward trend (χ2trend =8.45, P < .01); the prevalences of CMEEs were 1.19‰, 1.62‰, 1.80‰, 1.21‰, and 1.35‰, respectively, with no significant trend (χ2trend =0.09, P = .77). CMEEs were more common in males than females (1.60‰ vs 1.27‰, OR = 1.26, 95%CI: 1.12-1.41), in urban areas than in rural areas (1.77‰ vs 1.23‰, OR = 1.45, 95%CI: 1.29-1.62). The prevalences of CMEEs for maternal age < 20, 20-24, 25-29, 30-34, and ≥ 35 were 1.75‰, 1.27‰, 1.44‰, 1.47‰, and 1.58‰, respectively, with no significant difference (P > .05, reference: 25-29). Most CMEEs were diagnosed by clinical examinations (92.34%), and most CMEEs were diagnosed postpartum (within 7 days) (96.25%). In summary, we have presented the epidemiology of CMEEs in Hunan Province, China. CMEEs were more common in males than females, in urban areas than rural areas, whereas there was no significant difference in prevalence of CMEEs by maternal age. We inferred that CMEEs may be mainly related to genetics, and the mechanism needs to be examined in the future.
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