Non-alcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease worldwide. Caspase 8 and FADD-like apoptosis regulator (CFLAR) has been identified as a potent factor in mitigating non-alcoholic steatohepatitis (NASH) by inhibiting the N-terminal dimerization of apoptosis signal-regulating kinase 1 (ASK1). While arginine methyltransferase 1 (PRMT1) was previously reported to be associated with increased hepatic glucose production, its involvement in hepatic lipid metabolism remains largely unexplored. The interaction between PRMT1 and CFLAR and the methylation of CFLAR were verified by Co-IP and immunoblotting assays. Recombinant adenoviruses were generated for overexpression or knockdown of PRMT1 in hepatocytes. The role of PRMT1 in NAFLD was investigated in normal and high-fat diet-induced obese mice. In this study, we found a significant upregulation of PRMT1 and downregulation of CFLAR after 48h of fasting, while the latter significantly rebounded after 12h of refeeding. The expression of PRMT1 increased in the livers of mice fed a methionine choline-deficient (MCD) diet and in hepatocytes challenged with oleic acid (OA)/palmitic acid (PA). Overexpression of PRMT1 not only inhibited the expression of genes involved in fatty acid oxidation (FAO) and promoted the expression of genes involved in fatty acid synthesis (FAS), resulting in increased triglyceride accumulation in primary hepatocytes, but also enhanced the gluconeogenesis of primary hepatocytes. Conversely, knockdown of hepatic PRMT1 significantly alleviated MCD diet-induced hepatic lipid metabolism abnormalities and liver injury in vivo, possibly through the upregulation of CFLAR protein levels. Knockdown of PRMT1 suppressed the expression of genes related to FAS and enhanced the expression of genes involved in FAO, causing decreased triglyceride accumulation in OA/PA-treated primary hepatocytes in vitro. Although short-term overexpression of PRMT1 had no significant effect on hepatic triglyceride levels under physiological conditions, it resulted in increased serum triglyceride and fasting blood glucose levels in normal C57BL/6J mice. More importantly, PRMT1 was observed to interact with and methylate CFLAR, ultimately leading to its ubiquitination-mediated protein degradation. This process subsequently triggered the activation of c-Jun N-terminal kinase 1 (JNK1) and lipid deposition in primary hepatocytes. Together, these results suggested that PRMT1-mediated methylation of CFLAR plays a critical role in hepatic lipid metabolism. Targeting PRMT1 for drug design may represent a promising strategy for the treatment of NAFLD.

Schwann cells injury induced by high glucose (HG) contributes to the development of diabetic peripheral neuropathy (DPN). Honokiol has been reported to regulate glucose metabolism, however, its effect on DPN and the precise molecular mechanisms remain unclear. This study aimed to investigate the role of AMPK/SIRT1/PGC-1α axis in the protective effects of honokiol on DPN. The biochemical assay and JC-1 staining results demonstrated that honokiol reduced HG-induced oxidative stress and ferroptosis as well as mitochondrial dysfunction in Schwann cells. RT-qPCR and western blotting were utilized to investigate the mechanism of action of honokiol, and the results showed that HG-induced inhibition of AMPK/SIRT1/PGC-1α axis and changes of downstream gene expression profile were restored by honokiol. Moreover, silencing of Sirt1 by siRNA delivery markedly diminished the changes of gene expression profile induced by honokiol in HG-induced Schwann cells. More importantly, we found that administration of honokiol remarkably attenuated DPN via improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity in streptozotocin-induced diabetic rats. Collectively, these results demonstrate that honokiol can attenuate HG-induced Schwann cells injury and peripheral nerve dysfunction, suggesting a novel potential strategy for treatment of DPN.

High glucose induces Schwann cells death and neurotoxicity. Formononetin was originally found in Astragalus membranaceus and showed anti-tumor and anti-neuroinflammation properties. The aim of this study is to explore the molecular mechanism underlying the neuroprotective effects of formononetin and identify its direct protein target. The effects of formononetin on oxidative stress and mitochondrial dysfunction in Schwann cells induced by high glucose were investigated. High glucose treatment significantly induced oxidative stress, mitochondrial dysfunction and apoptosis in Schwann cells, while these effects were partially or completely prevented by co-treatment with formononetin. Mechanistically, we found that SIRT3/PGC-1α/SOD2 pathway was activated by formononetin under high glucose conditions as evidenced by western blotting. Knockdown of SIRT3 by siRNA delivery reversed the protective effects of formononetin on high glucose-induced Schwann cells injury and changes in expression profile of SIRT3 downstream target genes. Molecular docking, thermal shift assay and surface plasmon resonance assay revealed a direct binding between formononetin and SIRT3. Taken together, we identified a novel SIRT3 activator formononetin and revealed its beneficial effects on high glucose-induced neurotoxicity, suggesting that targeting SIRT3 in Schwann cells may be a new approach for treatment of peripheral nerve regeneration related diseases such as diabetic peripheral neuropathy.

It is well known that the excessive accumulation of lipid in hepatocytes is one of the important causes of non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to explore the effects of isosilybin on lipid metabolism in free fatty acids (FFAs) or TO901317-induced HepG2 cells. Cells were treated with FFAs (oleic acid: palmitic acid, 2:1) or TO901317 to induce steatosis in vitro. Intracellular triglyceride (TG) content was quantified using commercial assay kits. The mRNA and protein expression of genes involved in fatty acid uptake, synthesis and oxidation were analyzed by RT-qPCR and western blotting. Selected biological pathways regulated by isosilybin treatment were determined by GO and KEGG analysis. The results showed that isosilybin significantly reduced TG levels in FFAs- and TO901317-induced HepG2 cells. Further studies showed that isosilybin treatment decreased the mRNA and protein expression of lipid synthesis genes Srebp-1c, Pnpla3, Acc and Fas, as well as the mRNA expression of fatty acid uptake gene CD36, whereas increased the mRNA levels of lipid oxidation genes Pparα, Acox1 and Cpt1α, as well as the mRNA expression of lipid export gene Mttp, in FFAs-induced HepG2 cells. Moreover, TO901317 was employed to induce endogenous lipid synthesis and steatosis, and the expression of Srebp-1c and its target genes in TO901317-induced hepatocytes was basically similar to that in FFAs-induced hepatocytes following isosilybin treatment. We also observed the increased level of phosphorylated AMP kinase (AMPK) after isosilybin treatment, while this effect was reversed after further treatment with AMPK inhibitor, compound C. The results of GO and KEGG analysis indicated that the pathways of fatty acid and TG metabolism were regulated by isosilybin. Interestingly, we found that treatment with the diastereoisomer A of isosilybin increased TG level, while exposure to the diastereoisomer B of isosilybin decreased TG level in FFAs-induced HepG2 cells. The above results suggest that isosilybin can inhibit lipid synthesis and activate lipid oxidation through AMPK signaling pathway, thereby improving steatosis of hepatocytes, and isosilybin B is the basis of its active substance.

The electric and dielectric properties of Na0.5Bi4.50+xTi4Oy (x = -0.02, 0, 0.02) prepared by conventional mixed oxide route have been investigated by impedance spectroscopy (IS) over a wide temperature range. Single-phase bismuth layer-structured perovskite patterns were observed through X-ray diffraction of the three samples Na0.5Bi4.5Ti4O15, Na0.5Bi4.48Ti4Oy, and Na0.5Bi4.52Ti4Oy. The results show that the relative permittivity (epsilon r) increases with the increase in temperature and reaches its maximum at about 675celcius. With the continuous increase in temperature, the permittivity decreases gradually. Both relative permittivity and dielectric loss show great stability at the low-temperature zone. The ceramic of x = 0.02 with Ea of 1.09 eV has the maximum oxygen ionic transport number between 600 and 800celcius for all samples. And at this time, it has the maximum electrical conductivity. All the results indicated that Na0.5Bi4.50+xTi4Oy (x = -0.02, 0, 0.02) ceramics were promising base materials for high-temperature capacitor because of their high dielectric properties.

KxNa0.5-xBi4.46Ce0.04Ti4O15+y (x = 0, 0.04, 0.08, 0.12, 0.16, 0.20) ceramics were synthesized by solid state reaction. The microstructure and electrical properties of the solid solutions were characterized. It is found that the doping of appropriate amount of K improved the degree of lattice distortion of the material, and the characteristic parameter b/a of lattice distortion obtained the maximum value through structural refinement at x = 0.12. A defect dipole pair (K-Bi '' - V-o(..)) is formed by adjusting the defects of the material. The polarizability of defects is 4.88 x 10(-37)F.m(2). The formation of defect dipole pairs that deflect towards the direction of spontaneous polarization reduces the difficulty of polarization and improves the piezoelectric properties. Finally, the optimal piezoelectric coefficient (d(33)) of NBCT-xK ceramics is 23 pC/N, and the residual polarizability (2P(I)) is 4.14 mu C/cm(2). The values of residual polarization rate (2P(I)), piezoelectric coefficient (d(33)) and b/a show the same trend, which will gradually decrease when their value increases to a certain extent. The dielectric loss of all samples below 200 degrees C are lower than 0.01, and the dielectric constant is relatively flat below 400 degrees C. Moreover, the Curie temperature (T-c) of K(x)Na(0.5-x)Bi(4.46)Ce(0.04)Ti(4)O(15+y)based ceramics is increased to 686.0 degrees C, which will enable the ceramics to be used in oilfield logging, aerospace and military fields in high temperature environment.

Electrocaloric effects due to entropy change and dipole coupling upon electric field in second-order phase transition (tetragonal-cubic) ferroelectrics are investigated by a three-dimensional Devonshire's theory and statistic method. In diabatic condition, increase in vibration entropy to heat the ferroelectric is due to decreases in polarization entropy and configuration entropy of dipole reorientation in the specific directions. Coupling effect originated from the reorientation of dipoles accompany with electric hysteresis loop happens in the nearest neighbor dipoles parallel to electric field direction. Numerical simulations exhibit that polarization effect causes electrocaloric peak at the Curie's temperature independent of electric field, reorientation effect of dipole causes a shift of electrocaloric peak to high temperature with electric field, and coupling effect between dipoles gives rise to increase in electrocaloric effect with decreasing temperature. A method to predetermine the excellent electrocaloric effect of ferroelectrics from dielectric and/or polarization experimental results is proposed.

An electric hysteresis loop is derived according to dipole turning upon an applied electric field in 3D ferroelectrics by the Boltzmann statistic method via Gibbs free energy in the Devonshire's theory. The loop shape varies with temperature, dipole coupling, and applied maximum electric field, which provides a corresponding theoretical method to derive temperature dependent energy storage density. By numerical simulation the result demonstrates that energy storage density peak appears and shifts towards high temperature with increasing electric field, which is in good agreement with experimental results. A mechanism revealed that the high energy storage density in paraelectric phase, a state of zero spontaneous polarization, is ascribed to a huge increase in polarization induced by electric field around the Curie's temperature. Since ferroelectric dielectric constant is related to the induced polarization in principle, dielectric constant peak can be a direct indicator for the energy storage density peak.

Na0.5Bi4.5-xCexTi4O15(x = 0, 0.02, 0.04, 0.06, 0.08, 0.10) lead-free piezoelectric ceramics with high Curie temperatures are fabricated using the conventional solid-phase method. The effects of the Ce content on the phase structures, morphologies, and electrical properties of the Na(0.5)Bi(4.5-)(x)Ce(x)Ti(4)O(15)ceramics are systematically investigated. The appropriate content of Ce increasesb/aandc/aand induces the distortion of the crystal structure. The increasedb/aleads to a transverse asymmetry of the Na(0.5)Bi(4.5-)(x)Ce(x)Ti(4)O(15)ceramics, which facilitates the dipole flipping, thus enhancing the piezoelectric properties (d(33) = 20 pC/N). Although the improvedc/aincreases the degree of tetragonality of the Na(0.5)Bi(4.5-)(x)Ce(x)Ti(4)O(15)ceramic, which decreases the Curie temperature (T-C), theT(C)values of all samples are higher than 600 degrees C, considerably higher than the practical application temperature. The Ce doping significantly reduces the dielectric loss of the sample and increases its dielectric performance. The improvements in electric properties by the cerium doping can expand its use in high-temperature environments for oilfield logging, aerospace, and military applications.