Zheng Zhibing

Regulation of bacterial lipopolysaccharide in liver toxicity caused by chlorpromazine and Z24 in Sprague-Dawley rats

Objective To determine the characteristics and manifestations of liver toxicity induced by chlorpromazine (CPZ, a phenothiazine antipsychotic drug) and Z24 (an anticancer candidate drug) and to study the relationship between short-term inflammation and drug-induced liver toxicity through monitoring inflammation induced by low-dose lipopolysaccharides (LPS) and the hepatic toxicants CPZ and Z24. Methods A specific inhibitor of Kupffer cells, GdCl3, was used to probe the role of these cells in the development of liver toxicity. Interleukin-1 alpha (IL-1α) was evaluated to study the roles of hepatic non-parenchymal cells and inflammatory mediators in liver toxicity induced by CPZ and Z24, as well as the effect of LPS on drug-induced liver toxicity. In addition, the mechanism, process, steps and pathways of the influence exerted by hepatic non-parenchymal cells and inflammatory mediators are discussed. Results Treatment with 75 mg kg−1 CPZ caused significant changes in the blood biochemical index of liver toxicity, but this dosage did not have an effect on liver pathology. When 75 mg kg−1 CPZ was administered 2 h after an inflammatory response had been induced by 2 mg kg−1 LPS, the blood biochemical index of liver toxicity increased further, and liver injury lesions occurred. Treatment with 200 mg kg−1 Z24 significantly increased the blood biochemical index of liver toxicity and induced a significant pathological change in liver injuries. However, after 2 h of pretreatment with 2 mg kg−1 LPS followed by treatment with Z24, the blood biochemical index was normal, and pathological change was significantly reduced. Pretreatment with 10 mg kg−1 GdCl3 significantly inhibited the enhancement of CPZ-induced liver toxicity by LPS; however, the same treatment did not alter the protective effect of LPS against Z24-induced liver toxicity. Two hours of pretreatment with 1.25 μg kg−1 IL-1α significantly antagonized the liver toxicity induced by Z24; however, compared with the control group, a degree of liver toxicity was still observed. Conclusions When an organism is experiencing an inflammatory response, activation of Kupffer cells enhances CPZ-induced liver toxicity. The inflammatory response induced by LPS could be used to establish and study a screening model for idiosyncratic liver toxicity. Under inflammatory response conditions, activating endothelial cells and IL-1α might have a protective effect against Z24-induced liver toxicity.

Preparation of HI-6 absorptive human serum albumin nanoparticles and evaluation of its reactivation efficacy on inhibited brain AChE in soman-intoxicated mice

It was essential to rapidly reactivate and restore the function of the inhibited acetylcholinesterase(AChE) in the treatment of nerve agents poisoning. However, the blood-brain barrier (BBB) restricts the rapid transport of reactivators from the blood into the brain in therapeutically relevant concentrations. In this study, human serum albumin nanoparticles(HSA NPs) were prepared via desolvent method; HI-6, the known reactivator with higher reactivating efficiency were bound to HSA NPs through electrostatic interaction; at last, on zebrafish BBB model and soman-intoxicated mice, the permeability on BBB and the reactivation on inhibited brain AChE of nanoparticulate oxime formulations were evaluated. All characterization data revealed that HSA NPs loaded with HI-6 had met the basic demand for nanodrug therapy. Compared with free HI-6, HSA NPs loaded HI-6 could cross the BBB and improve the reactivating rates two times, suggesting HSA NPs could carry HI-6 into CNS successfully. In brief, we improved and established a method to prepare the brain-targeted nanoparticles with small-size, low-toxicity and high-efficiency, the targeted drug based on this method could efficiently release and rapidly antagonize the nerve agents poisoning.