Dose-related liver injury of Geniposide associated with the alteration in bile acid synthesis and transportation.

Fructus Gardenia (FG), containing the major active constituent Geniposide, is widely used in China for medicinal purposes. Currently, clinical reports of FG toxicity have not been published, however, animal studies have shown FG or Geniposide can cause hepatotoxicity in rats. We investigated Geniposide-induced hepatic injury in male Sprague-Dawley rats after 3-day intragastric administration of 100 mg/kg or 300 mg/kg Geniposide. Changes in hepatic histomorphology, serum liver enzyme, serum and hepatic bile acid profiles, and hepatic bile acid synthesis and transportation gene expression were measured. The 300 mg/kg Geniposide caused liver injury evidenced by pathological changes and increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and γ-glutamytransferase (γ-GT). While liver, but not sera, total bile acids (TBAs) were increased 75% by this dose, dominated by increases in taurine-conjugated bile acids (t-CBAs). The 300 mg/kg Geniposide also down-regulated expression of Farnesoid X receptor (FXR), small heterodimer partner (SHP) and bile salt export pump (BSEP). In conclusion, 300 mg/kg Geniposide can induce liver injury with associated changes in bile acid regulating genes, leading to an accumulation of taurine conjugates in the rat liver. Taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA) as well as tauro-α-muricholic acid (T-α-MCA) are potential markers for Geniposide-induced hepatic damage

MTHFR Gene Polymorphism Association With Psoriatic Arthritis Risk and the Efficacy and Hepatotoxicity of Methotrexate in Psoriasis.

Aims To assess whether MTHFR rs1801131 and rs1801133 SNPs are associated with concomitant psoriatic arthritis (PsA) and investigate the efficacy and hepatotoxicity of MTX in patients with psoriasis in the Han Chinese population. Methods This prospective, single-arm, interventional study recruited a total of 309 patients with psoriasis, 163 with psoriatic arthritis and 146 without psoriatic arthritis, who completed a 12-week MTX treatment and 1,031 healthy controls. Patients' characteristics including age, gender, disease duration, height, weight, smoking status, alcohol consumption, medical history, disease severity and liver function test results were accessed and recorded. Single nucleotide polymorphism (SNP) genotyping of rs1801131 and rs1801133 in the MTHFR gene was performed. Results The rs1801133 CC genotype was more frequent in patients with PsA than those with PsO and healthy controls (42.3% vs. 28.8% vs. 33.1%, p < 0.05). The 90% reduction from baseline PASI score (PASI 90) response rates to MTX were significantly higher in patients with the rs1801133 TT genotype than those with the CT and CC genotype (33.96% vs. 19.31% vs. 14.41%, OR = 2.76, p = 0.006). The rs1801133 CT+TT genotype was more frequent in PsA patients with abnormal liver function than in those with normal liver function (p < 0.05). In addition, patients with the rs1801131 CT genotype had lower PASI 75 response rates to MTX (OR = 0.49, p = 0.01), and lower risk of ALT elevation (OR = 0.46, p = 0.04). Conclusions This study provided some evidence for MTHFR polymorphism association with the risk of PsA and the efficacy and hepatotoxicity of the low-dose MTX in the Chinese population. Given the relatively small sample size and potentially missed diagnosis of PsA, the results from this study warrant further investigation

Market investigation of basic parameters for exposure assessment of contact materials for nut-seed food in China

Objective To establish the basic parameters for exposure assessment of contact materials for nut-seed food in China. Methods The contact area method was used to study the contact materials of nut-seed food in this study. Based on the contact area values, ratio of contact areas and unit mass were obtained. Results Through investigation and analysis, 114 kinds of nut-seed food were sampled, and 3 648 related data were obtained. Food contact materials of nut-seed food on the market mainly included aluminum, polyethylene, polyethylene terephthalate, polypropylene, polystyrene and coating. The average contact area per unit mass or volume (S/V) was 21.29 dm2/kg, the median was 13.40 dm2/kg, P5 was 1.11 dm2/kg, and P95 was 67.46 dm2/kg. Conclusion The basic parameters of nut-seed food contact materials could provide data support for the safety assessment in China

Physical Characterization and Volatile Organic Compound Monitoring of Recycled Polyethylene Terephthalate under Mechanical Recycling

In this study, physical characterization and monitoring of volatile organic compounds (VOCs) were investigated on recycled polyethylene terephthalate (rPET) from a mechanical recycling process and rPET bottles made with different rPET contents, with the aim of tracing the source of rPET and assessing its safety when use as a food contact material. It was found that rPET had a similar thermal stability to that of virgin PET (vPET). rPET bottles did not show any significant changes in groups or structure and exhibit similar crystallization and melting behaviors to vPET. However, there were minor mechanical scratches in the surface micromorphology of rPET bottles, and the color of rPET bottles became darker, greener and yellower as the content of recycled material increased. The solid-state polycondensation process was found to play an important role in the removal of VOCs, as detected by headspace gas chromatography-mass spectrometry (HS-GC-MS), resulting in a very small amount of residual VOCs in rPET. Four VOCs (acetaldehyde, glycol and nonanal at levels less than 1.00 mg/kg; 2-methyl-1,3 dioxolane at levels of 1.72-5.76 mg/kg) were detected in the rPET bottles. This study shows that rPET bottles are qualified for reuse in food contact in terms of thermal properties, structure, morphology and VOC residues, although there is variability in color

Salsolinol Facilitates Glutamatergic Transmission to Dopamine Neurons in the Posterior Ventral Tegmental Area of Rats

Although in vivo evidence indicates that salsolinol, the condensation product of acetaldehyde and dopamine, has properties that may contribute to alcohol abuse, the underlying mechanisms have not been fully elucidated. We have reported previously that salsolinol stimulates dopamine neurons in the posterior ventral tegmental area (p-VTA) partly by reducing inhibitory GABAergic transmission, and that ethanol increases glutamatergic transmission to VTA-dopamine neurons via the activation of dopamine D1 receptors (D1Rs). In this study, we tested the hypothesis that salsolinol stimulates dopamine neurons involving activation of D1Rs. By using whole-cell recordings on p-VTA-dopamine neurons in acute brain slices of rats, we found that salsolinol-induced increase in spike frequency of dopamine neurons was substantially attenuated by DL-2-amino-5-phosphono-valeric acid and 6, 7-dinitroquinoxaline-2, 3-dione, the antagonists of glutamatergic N-Methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Moreover, salsolinol increased the amplitude of evoked excitatory postsynaptic currents (EPSCs) and the frequency but not the amplitude of spontaneous EPSCs. Additionally, SKF83566, a D1R antagonist attenuated the salsolinol-induced facilitation of EPSCs and of spontaneous firing of dopamine neurons. Our data reveal that salsolinol enhances glutamatergic transmission onto dopamine neurons via activation of D1Rs at the glutamatergic afferents in dopamine neurons, which contributes to salsolinol's stimulating effect on p-VTA dopamine neurons. This appears to be a novel mechanism which contributes toward rewarding properties of salsolinol

Mitogen-activated protein kinase inhibition-induced modulation of epidermal growth factor receptor signaling in human head and neck squamous cell carcinoma

Background: Epidermal growth factor receptor (EGFR) overexpression is one of the most notable characteristics in head and neck squamous cell carcinoma (HNSCC). The MAPK kinase (MEK) inhibitor trametinib has shown efficacy to treat HNSCC; however, the molecular mechanism remains unclear. Methods: HNSCC lines, mouse models, Western blot, and flow cytometry were employed to analyze the anticancer effects of trametinib. Results: The JHU-011, JHU-022, and JHU-029 HNSCC cells with different genetic alterations were highly susceptible to trametinib. Trametinib effectively reduced EGFR expression, which was accompanied by the reduction of pro-survival protein MYC, and the increased expression of a MYC-targeted cyclin-dependent kinase inhibitor p27kip1 and pro-apoptotic protein BIM. Trametinib resulted in G1 arrest of the cells, markedly reduced cell numbers in S phase, and significantly increased apoptosis. In mouse models, trametinib strongly inhibited tumors growth. Conclusions: The MAPK–ERK signaling inhibition by trametinib may target EGFR and the downstream proteins against HNSCC

Effect of austenitizing temperature on the microstructure and mechanical properties of Nb–Ti microalloyed steel

The effect of austenitizing temperature on the microstructure and mechanical properties of Nb–Ti microalloyed steel was investigated. Steels were subjected to different austenitizing treatments (temperatures ranging from 850 °C to 1250 °C for 5-120 min) and rolled after being austenitized at different temperatures (i.e. 1020 °C, 1070 °C and 1150 °C). The results showed that austenite grain coarsening temperature was around 1000 °C. The mean grain size of the rolled steels initially increased and then decreased, but the ferrite content decreased with increasing austenitizing temperature. The precipitates in the prior austenite and rolled steel were both complex Nb–Ti carbonitrides. As the austenitizing temperature increased from 1020 °C to 1150 °C, most precipitates were dissolved and re-precipitated as dispersive particles with mean size decreasing from 30 nm to 10 nm. Meanwhile, the 80 nm to 100 nm rectangular Ti-rich carbonitrides were not dissolved and varied during the subsequent cooling process.The Yield strength and ultimate tensile strength increased but the elongation and reduction in area (in percent) decreased with the elevated austenitizing temperature