TPPU protects tau from HO-induced hyperphosphorylation in HEK293/tau cells by regulating PI3K/AKT/GSK-3β pathway / 华中科技大学学报（医学）（英德文版）

Neurofibrillary pathology of abnormally hyperphosphorylated tau is a hallmark of Alzheimer's disease (AD) and other tauopathies. Phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase-3 beta (GSK-3β) signaling pathway is pivotal for tau phosphorylation. Inhibition of soluble epoxide hydrolase (sEH) metabolism has been shown to effectively increase the accumulation of epoxyeicosatrienoic acids (EETs), which are cytochrome P450 metabolites of arachidonic acid and have been demonstrated to have neuroprotective effects. However, little is known about the role of sEH in tau phosphorylation. The present study investigated the role of a sEH inhibitor, 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl] urea (TPPU), on HO-induced tau phosphorylation and the underlying signaling pathway in human embryonic kidney 293 (HEK293)/Tau cells. We found that the cell viability was increased after TPPU treatment compared to control in oxidative stress. Western blotting and immunofluorescence results showed that the levels of phosphorylated tau at Thr231 and Ser396 sites were increased in HO-treated cells but dropped to normal levels after TPPU administration. HOinduced an obvious decreased phosphorylation of GSK-3β at Ser9, an inactive form of GSK-3β, while there were no changes of phosphorylation of GSK-3β at Tyr216. TPPU pretreatment maintained GSK-3β Ser 9 phosphorylation. Moreover, Western blotting results showed that TPPU upregulated the expression of p-Akt. The protective effects of TPPU were found to be inhibited by wortmannin (WT, a specific PI3K inhibitor). In conclusion, these results suggested that the protective effect of TPPU on HO-induced oxidative stress is associated with PI3K/Akt/GSK-3β pathway.

Role of transient receptor potential vanilloid 4 in the effect of osmotic pressure on myocardial contractility in rat / 生理学报

The aim of the present study was to investigate the influence of osmotic pressure on myocardial contractility and the possible mechanism. Electrical stimulation was used to excite papillary muscles of the left ventricle of Sprague-Dawley (SD) rats. The contractilities of myocardium in hyposmotic, isosmotic, and hyperosmotic perfusates were recorded. The influences of agonist and antagonist of the transient receptor potential vanilloid 4 (TRPV4) on the contractility of myocardium under hyposmotic, isosmotic and hyperosmotic conditions were observed. The results were as follows: (1) Compared with that under isosmotic condition (310 mOsm/L), the myocardial contractility was increased by 11.5%, 21.5% and 25.0% (P<0.05) under hyposmotic conditions when the osmotic pressure was at 290, 270 and 230 mOsm/L, respectively; and was decreased by 16.0%, 23.7% and 55.2% (P<0.05) under hyperosmotic conditions when the osmotic pressure was at 350, 370 and 390 mOsm/L, respectively. (2) When ruthenium red (RR), an antagonist of TRPV4, was added to the hyposmotic perfusate (270 mOsm/L), the positive inotropic effect of hyposmia was restrained by 36% (P<0.01); and when RR was added to the hyperosmotic perfusate (390 mOsm/L), the inhibitory effect of hyperosmia on myocardial contractility was increased by 56.1% (P<0.01). (3) When 4-α-phorbol-12,13-didecanoate (4α-PDD), an agonist of TRPV4, was added to the isosmotic perfusate (310 mOsm/L), the myocardial contractility did not change; and when 4α-PDD was added to the hyperosmotic perfusate (390 mOsm/L), the inhibition of myocardial contractility by hyperosmia was increased by 27.1% (P<0.01). These results obtained indicate that TRPV4 is possibly involved in the osmotic pressure-induced inotropic effect.