TNEA therapy promotes the autophagic degradation of NLRP3 inflammasome in a transgenic mouse model of Alzheimer's disease via TFEB/TFE3 activation.

BACKGROUND: The impairment in the autophagy-lysosomal pathway (ALP) and the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome represent two molecular events leading to neurodegeneration and neuroinflammation in Alzheimer's disease (AD), a devastating neurodegenerative disorder without a cure. Previously we demonstrated the cognitive-enhancing effect of a combined electroacupuncture (EA) therapy termed TNEA in a transgenic mouse model of AD, involving activation of transcription factor EB (TFEB), a master regulator of ALP. However, whether and how TNEA inhibits NLRP3 inflammasome via TFEB-mediated ALP in AD remains to be investigated. METHODS: 5xFAD mice overexpressing amyloid-ß (Aß) were treated with TNEA or EA on its composing acupoints (GB13 and GV24). The changes in the signaling pathways regulating NLRP3 inflammasome, the association of NLRP3 inflammasome with ALP, and the roles of TFEB/TFE3 in mice brains were determined by immunoblots, immunohistochemistry and AAV-mediated knockdown assays. RESULTS: TNEA inhibits the activation of NLRP3 inflammasome and the release of active interleukin 1ß (IL1B) in the hippocampi of 5xFAD mice. Mechanistically, TNEA promoted the autophagic degradation of inflammasome components via activating both TFEB and TFE3 by modulating kinases including AMPK and AKT. The composing acupoints in TNEA showed synergistic effects on regulating these molecular events and memory improvement. CONCLUSION: Our findings suggest that TNEA attenuates AD-associated memory impairment via promoting TFEB/TFE3-mediated autophagic clearance of Aß and NLRP3 inflammasome, and partially reveal the molecular basis of combined acupoints therapy originated from ancient wisdom.

Influence of stem and leaf phenotypes, physiological responses and cellular ultrastructure on defoliated sugarcane cultivars.

Defoliation is a primary agronomic traits, its variation depends on different plant species or cultivars. The present article assess the leaf morphological responses, oxidative metabolites and enzymatic activities at sheath base of sugarcane cultivars during defoliation stage of plant leaves. The mature leaf sheath of GT47 strongly wrapped to the stem, and no stem was exposed. The upper and lower edges of the immature fusing abscission zone were parallel, and slightly lower browning area (+ 3 to + 7 leaf position). The ROC22 cultivar was monitored highest leaf sheath-based cellulose and lignin content, followed by GT60 and GT47. Peroxidase activity was higher in leaf sheath base edge (ROC22) as compare to other cultivars. The malondialdehyde content was found highest in GT60, followed by ROC22, and GT47. The exo-ß-1,4-glucanase/ cellobiohydrolase activity was found highest in the margin of GT47 than lateral and medial axis of ROC22 and GT60. The axis activity increased exponentially, and ROC22 gradually decreased from the periphery of the mid-axis and lower than GT47 and GT60 in the lateral and mid-axis of leaf. In conclusion, the mature leaves are easy to defoliate mainly loose leaf sheaths, large leaf sheath inclination angles, more deformation during the growth period of the abscission zone, early with large cracks, and slow browning process. Leaf sheaths with high fibre and lignin content showed significant hardness and thickness. The sugarcane cultivars showed positive correlation between peroxidase and malondialdehyde content with the browning process at the base of mature leaf sheaths.