Dexmedetomidine hydrochloride inhibits hepatocyte apoptosis and inflammation by activating the lncRNA TUG1/miR-194/SIRT1 signaling pathway.

BACKGROUND: Liver injury seriously threatens the health of people. Meanwhile, dexmedetomidine hydrochloride (DEX) can protect against liver injury. However, the mechanism by which Dex mediates the progression of liver injury remains unclear. Thus, this study aimed to investigate the function of DEX in oxygen and glucose deprivation (OGD)-treated hepatocytes and its underlying mechanism. METHODS: In order to investigate the function of DEX in liver injury, WRL-68 cells were treated with OGD. Cell viability was measured by MTT assay. Cell apoptosis was detected by flow cytometry. Inflammatory cytokines levels were measured by ELISA assay. The interaction between miR-194 and TUG1 or SIRT1 was detected by dual-luciferase reporter. Gene and protein levels were measured by qPCR or western blotting. RESULTS: DEX notably reversed OGD-induced inflammation and apoptosis in WRL-68 cell. Meanwhile, the effect of OGD on TUG1, SIRT1 and miR-194 expression in WRL-68 cells was reversed by DEX treatment. However, TUG1 knockdown or miR-194 overexpression reversed the function of DEX in OGD-treated WRL-68 cells. Moreover, TUG1 could promote the expression of SIRT1 by sponging miR-194. Furthermore, knockdown of TUG1 promoted OGD-induced cell growth inhibition and inflammatory responses, while miR-194 inhibitor or SIRT1 overexpression partially reversed this phenomenon. CONCLUSIONS: DEX could suppress OGD-induced hepatocyte apoptosis and inflammation by mediation of TUG1/miR-194/SIRT1 axis. Therefore, this study might provide a scientific basis for the application of DEX on liver injury treatment.

Antioxidant and antiproliferative activities of hydroxyl-substituted Schiff bases.

Eight hydroxyl-substituted Schiff bases with the different number and position of hydroxyl group on the two asymmetric aromatic rings (A and B rings) were prepared by the reaction between the corresponding aromatic aldehyde and aniline. Their antioxidant effects against the stable galvinoxyl radical (GO(.)) in ethyl acetate and methanol, and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH)-induced DNA strand breakage, and their antiproliferative effects on human hepatoma HepG2 cells, were investigated. Structure-activity relationship analysis demonstrates that o-dihydroxyl groups on the aromatic A ring and 4-hydroxyl group attached to the aromatic B ring contribute critically to the antioxidant and antiproliferative activities.

Antioxidant activity of alpha-pyridoin and its derivatives: possible mechanism.

alpha-Pyridoin (1, 1,2-di(2-pyridyl)-1,2-ethenediol) is a unique enediol antioxidant. To explore the detailed antioxidant mechanism of alpha-pyridoin, we synthesized alpha-pyridoin and its 5,5'- or 6,6'-bis-substituted derivatives (2-7) and compared their capacities to scavenge galvinoxyl radical (GO*) and protect human red blood cells (RBCs) from oxidative haemolysis. It was found that the compounds (5 and 6) with a methyl or methoxy group at the 5-position exhibit significantly higher GO*-scavenging and anti-haemolysis activities than other derivatives and vitamin C. Kinetic analysis of the GO*-scavenging reaction and the effect of added base on the reaction rate revealed that in ethyl acetate, the reaction occurs primarily by the direct hydrogen atom transfer (HAT mechanism). However, in ethanol that supports ionization, the kinetics of the process is mostly governed by sequential proton loss electron transfer (SPLET mechanism).

Hydroxycinnamic acids as DNA-cleaving agents in the presence of Cu(II) ions: mechanism, structure-activity relationship, and biological implications.

The effectiveness of hydroxycinnamic acids (HCAs), that is, caffeic acid (CaA), chlorogenic acid (ChA), sinapic acid (SA), ferulic acid (FA), 3-hydroxycinnamic acid (3-HCA), and 4-hydroxycinnamic acid (4-HCA), as pBR322 plasmid DNA-cleaving agents in the presence of Cu(II) ions was investigated. Compounds bearing o-hydroxy or 3,5-dimethoxy groups on phenolic rings (CaA, SA, and ChA) were remarkably more effective at causing DNA damage than the compounds bearing no such groups; furthermore, CaA was the most active among the HCAs examined. The involvement of reactive oxygen species (ROS) and Cu(I) ions in the DNA damage was affirmed by the inhibition of the DNA breakage by using specific scavengers of ROS and a Cu(I) chelator. The interaction between CaA and Cu(II) ions and the influence of ethylenediaminetetraacetic acid (EDTA), the solvent, and pH value on the interaction were also studied to help elucidate the detailed prooxidant mechanism by using UV/Vis spectroscopic analysis. On the basis of these observations, it is proposed that it is the CaA phenolate anion, instead of the parent molecule, that chelates with the Cu(II) ion as a bidentate ligand, hence facilitating the intramolecular electron transfer to form the corresponding CaA semiquinone radical intermediate. The latter undergoes a second electron transfer with oxygen to form the corresponding o-quinone and a superoxide, which play a pivotal role in the DNA damage. The intermediacy of the semiquinone radical was supported by isolation of its dimer from the Cu(II)-mediated oxidation products. Intriguingly, CaA was also the most cytotoxic compound among the HCAs toward human promyelocytic leukemia (HL-60) cell proliferation. Addition of exogenous Cu(II) ions resulted in an effect dichotomy on cell viability depending on the concentration of CaA; that is, low concentrations of CaA enhanced the cell viability and, conversely, high concentrations of CaA almost completely inhibited the cell proliferation. On the other hand, when superoxide dismutase was added before, the two stimulation effects of exogenous Cu(II) ions were significantly ameliorated, thus clearly indicating that the oxidative-stress level regulates cell proliferation and death. These findings provide direct evidence for the antioxidant/prooxidant mechanism of cancer chemoprevention.