Saikosaponins induced hepatotoxicity in mice via lipid metabolism dysregulation and oxidative stress: a proteomic study

Background Radix Bupleuri (RB) has been popularly used for treating many liver diseases such as chronic hepatic inflammation and viral Hepatitis in China. Increasing clinical and experimental evidence indicates the potential hepatotoxicity of RB or prescriptions containing RB. Recently, Saikosaponins (SS) have been identified as major bioactive compounds isolated from RB, which may be also responsible for RB-induced liver injury. Methods Serum AST, ALT and LDH levels were determined to evaluate SS-induced liver injury in mice. Serum and liver total triglyceride and cholesterol were used to indicate lipid metabolism homeostasis. Liver ROS, GSH, MDA and iNOS were used to examine the oxidative stress level after SS administration. Western blot was used to detect CYP2E1 expression. A 8-Plex iTRAQ Labeling Coupled with 2D LC - MS/MS technique was applied to analyze the protein expression profiles in livers of mice administered with different doses of SS for different time periods. Gene ontology analysis, cluster and enrichment analysis were employed to elucidate potential mechanism involved. HepG2 cells were used to identify our findings in vitro. Results SS dose- and time-dependently induced liver injury in mice, indicated by increased serum AST, ALT and LDH levels. According to proteomic analysis, 487 differentially expressed proteins were identified in mice administrated with different dose of SS for different time periods. Altered proteins were enriched in pathways such as lipid metabolism, protein metabolism, macro molecular transportation, cytoskeleton structure and response to stress. SS enhanced CYP2E1 expression in a time and dose dependent manner, and induced oxidative stress both in vivo and in vitro. Conclusion Our results identified hepatotoxicity and established dose-time course-liver toxicity relationship in mice model of SS administration and suggested potential mechanisms, including impaired lipid and protein metabolism and oxidative stress. The current study provides experimental evidence for clinical safe use of RB, and also new insights into understanding the mechanism by which SS and RB induced liver injury

Composite Implicit General Iterative Process for a Nonexpansive Semigroup in Hilbert Space

Let C be nonempty closed convex subset of real Hilbert space H. Consider C a nonexpansive semigroup ℑ={T(s):s≥0} with a common fixed point, a contraction f with coefficient 00. Let 0<γ<γ¯/α. It is proved that the sequence {xn} generated iteratively by xn=(I−αnA)(1/tn)∫0tnT(s)ynds+αnγf(xn),yn=(I−βnA)xn+βnγf(xn) converges strongly to a common fixed point x∗∈F(ℑ) which solves the variational inequality 〈(γf−A)x∗,z−x∗〉≤0 for all z∈F(ℑ)

Adaptive Sliding Mode Fault Tolerant Control for Autonomous Vehicle With Unknown Actuator Parameters and Saturated Tire Force Based on the Center of Percussion

With consideration of tire force saturation in vehicle motions, a novel path-following controller is developed for autonomous vehicles with unknown-bound disturbances and unknown actuator parameters. An adaptive sliding-mode fault-tolerant control (ASM-FTC) strategy is designed to stabilize the path-following errors without any information of disturbance boundaries, actuator fault boundaries and steering ratio from the steering wheel to the front wheels. By selecting the distance from the center of gravity to the center of percussion as the preview length, the effects of the lateral rear-tire force are decoupled and cancelled out, and then the preview error, which represents the path-following performance, can be only commanded by the front-tire force. To further address the issue of unknown tire-road friction limits, a modified ASM-FTC strategy is presented to improve the path-following performance as the lateral tire force is saturated. Simulation results show that the modified ASM-FTC controller demonstrates superior tracking performance over the normal ASM-FTC while the autonomous vehicle follows desired paths

Plant Species Rather Than Climate Greatly Alters the Temporal Pattern of Litter Chemical Composition During Long-Term Decomposition

A feedback between decomposition and litter chemical composition occurs with decomposition altering composition that in turn influences the decomposition rate. Elucidating the temporal pattern of chemical composition is vital to understand this feedback, but the effects of plant species and climate on chemical changes remain poorly understood, especially over multiple years. In a 10-year decomposition experiment with litter of four species (Acer saccharum, Drypetes glauca, Pinus resinosa, and Thuja plicata) from four sites that range from the arctic to tropics, we determined the abundance of 11 litter chemical constituents that were grouped into waxes, carbohydrates, lignin/tannins, and proteins/peptides using advanced 13C solid-state NMR techniques. Decomposition generally led to an enrichment of waxes and a depletion of carbohydrates, whereas the changes of other chemical constituents were inconsistent. Inconsistent convergence in chemical compositions during decomposition was observed among different litter species across a range of site conditions, whereas one litter species converged under different climate conditions. Our data clearly demonstrate that plant species rather than climate greatly alters the temporal pattern of litter chemical composition, suggesting the decomposition-chemistry feedback varies among different plant species