| Evidence Sentence: |
Preventive electroacupuncture alleviated memory impairment, decreased tau hyperphosphorylation, and reduced glycogen synthase kinase-3beta protein and mRNA expression levels in the brainstem dorsal raphe nucleus, where intracellular neurofibrillary tangle lesions first occur. |
| Evidence Sentence: |
In addition, the DNA methylation level in the promoter region of the glycogen synthase kinase-3beta gene was increased. |
| Evidence Sentence: |
Our results suggest that preventive electroacupuncture treatment alleviates cognitive impairment in aging rats probably by affecting the epigenetic modification of the glycogen synthase kinase-3beta gene in the dorsal raphe nucleus. |
| Evidence Sentence: |
PEA and PMA inhibit GSK-3beta in the DRN in the rat model of D-gal-induced aging |
| Evidence Sentence: |
To investigate the mechanism underlying D-gal-induced tau hyperphosphorylation, western blotting was performed to detect the expression levels of GSK-3beta and to assess its activation state. |
| Evidence Sentence: |
As shown in Figure 3, increased GSK-3beta activity, as evidenced by elevated levels of GSK-3beta and GSK-3beta-pTyr216, and decreased levels of GSK-3beta-pSer9 were observed in the DRN after intraperitoneal injection of D-gal, suggesting that GSK-3beta activity is upregulated in the DRN in rats with D-gal-induced aging. |
| Evidence Sentence: |
Compared with the model group, the levels of total GSK-3beta and GSK-3beta-pTyr216 were significantly decreased in rats in the PEA + inhibition, PMA and PEA groups (P < 0.01), while no statistically significant difference was observed between the inhibitor and model groups (P > 0.05). |
| Evidence Sentence: |
The level of inactive GSK-3beta-pSer9 in the inhibitor group was reduced compared with the model group (P < 0.01). |
| Evidence Sentence: |
Furthermore, the levels of GSK-3beta-pSer9 in the PMA and PEA groups were increased compared with the model group (P < 0.01). |
| Evidence Sentence: |
Unexpectedly, no significant differences were detected between the model and PEA + inhibitor groups, but the level of GSK-3beta-pSer9 was higher in the PEA group compared with the PEA + inhibitor and inhibitor groups (P < 0.01). |
| Evidence Sentence: |
No statistically significant difference in total GSK-3beta, GSK-3beta-pTyr216 or GSK-3beta-pSer9 was observed between the PMA and PEA groups (P > 0.05). |
| Evidence Sentence: |
These results indicate that PMA and PEA treatments both inhibit the activity of GSK-3beta, thereby decreasing tau phosphorylation levels in the DRN in the rat model of D-gal-induced aging. |
| Evidence Sentence: |
PEA and PMA increase GSK-3beta gene promoter methylation levels and decrease GSK-3beta mRNA expression in the DRN in the rat model of D-gal-induced aging |
| Evidence Sentence: |
Therefore, we next studied the levels of cytosine methylation in the promoter region of the GSK-3beta gene in the DRN (Figure 4A). |
| Evidence Sentence: |
As shown in Figure 4C, intraperitoneal injection of D-gal decreased the methylation level in the CpG islands of the GSK-3beta gene promoter, and upregulated the expression of GSK-3beta mRNA in the DRN. |
| Evidence Sentence: |
As shown in Figure 4B, compared with the model group, GSK-3beta mRNA expression was increased in the inhibitor group (P < 0.05), but was decreased in the PEA + inhibitor (P < 0.01), PMA (P < 0.01) and PEA groups (P < 0.01). |
| Evidence Sentence: |
Unexpectedly, GSK-3beta mRNA level in the PEA group was higher than that in the PMA group (P < 0.01), suggesting that other epigenetic modulatory pathways could also be involved in the PEA-induced silencing of the GSK-3beta gene. |
| Evidence Sentence: |
These findings indicate that PEA and PMA treatments inhibit the transcription of the GSK-3beta gene in the DRN, in turn decreasing tau phosphorylation levels, in the rat model of D-gal-induced aging. |
| Evidence Sentence: |
These results indicate that PEA increases GSK-3beta DNA methylation levels by upregulating the expression of DNMT1, and that PEA is more effective than PMA. |
