ABSTRACT
Tacrolimus (TAC), also called FK506, is one of the classical immunosuppressants to prevent allograft rejection after liver transplantation. However, it has been proved to be associated with post-transplant hyperlipemia. The mechanism behind this is unknown, and it is urgent to explore preventive strategies for hyperlipemia after transplantation. Therefore, we established a hyperlipemia mouse model to investigate the mechanism, by injecting TAC intraperitoneally for eight weeks. After TAC treatment, the mice developed hyperlipemia (manifested as elevated triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c), as well as decreased high-density lipoprotein cholesterol (HDL-c)). Accumulation of lipid droplets was observed in the liver. In addition to lipid accumulation, TAC induced inhibition of the autophagy-lysosome pathway (microtubule-associated protein 1 light chain 3β (LC3B) II/I and LC3B II/actin ratios, transcription factor EB (TFEB), protein 62 (P62), and lysosomal-associated membrane protein 1 (LAMP1)) and downregulation of fibroblast growth factor 21 (FGF21) in vivo. Overexpression of FGF21 may reverse TAC-induced TG accumulation. In this mouse model, the recombinant FGF21 protein ameliorated hepatic lipid accumulation and hyperlipemia through repair of the autophagy-lysosome pathway. We conclude that TAC downregulates FGF21 and thus exacerbates lipid accumulation by impairing the autophagy-lysosome pathway. Recombinant FGF21 protein treatment could therefore reverse TAC-caused lipid accumulation and hypertriglyceridemia by enhancing autophagy.
Subject(s)
Animals , Mice , Tacrolimus , Liver , Cholesterol, LDL , Autophagy , Disease Models, AnimalABSTRACT
Schisandra chinensis is a commonly used hepatoprotective medicine in clinic. Previous studies have showed that Schisandrae Chinensis Fructus has dual effects on the activity of CYPs. Short-term administration of Schisandrae Chinensis Fructus may inhibit CYP450s activity, while long-term administration may up-regulate CYP activity. High CYP450s activity level may increase the frequency of reactive metabolites-induced liver injury. It remains unclear how long-term administration of Schisandrae Chinensis Fructus may affect acetaminophen-induced acute hepatotoxicity. After oral administration of Schisandrae Chinensis Fructus extract (0.5-2.0 g·kg⁻¹) for 21 d, the activity of CYPs, Nrf2, HO-1, GST expressions, SOD and GST activity as well as glutathione level of SD rats were up-regulated. Besides, Schisandrae Chinensis Fructus extract ameliorated APAP (500 mg·kg⁻¹)-induced acute hepatotoxicity in a dose-dependent manner, as evidenced by decrease in ALT, AST, and MDA level and increase in GSH level (<0.05). What's more, the liver histopathology was alleviated, and cleaved caspase-3 expression was decreased. Besides, the increase of N-acetyl-p-benzoquinoneimine-GSH (reactive metabolite of acetaminophen) formation was observed in Schisandrae Chinensis Fructus extract groups. In conclusion, the present study indicated that the effects of Schisandrae Chinensis Fructuson acetaminophen-induced hepatotoxicity may rely on the Nrf2 signal pathway activation, and less depends on the increase in CYP450s activity.
Subject(s)
Animals , Rats , Acetaminophen , Chemical and Drug Induced Liver Injury , Cytochrome P-450 Enzyme System , Drugs, Chinese Herbal , Liver , NF-E2-Related Factor 2 , Rats, Sprague-DawleyABSTRACT
Objective To detect the expression of CD 44 +/CD24 -and E-cadherin and vimentin in non-small cell lung cancer and its clinical prognostic relevance .Methods By immunohistochemistry , detecting , 500 cases of non-small cell lung cancer E -cadherin ,Vimentin and CD44 +/CD24 -expressions′correlation ,we analyzed the relationship with non -small cell lung cancer .Results In non-small cell lung cancer , vimentin was related to tissue differentiation,TNM staging(P<0.05);there was relationship between CD44 +/CD24 -and EMT by E-cadherin expression(P <0.05);CD44 +/CD24 -expression was related to lymph node metastasis , differentiation(P<0.05);their expressions were not obviously related to age ,sex,smoking history,clinical patho-logical type .The survival time of CD44 +/CD24 -high expression in NSCLC was significantly shorter than lower expression in NSCLC(P<0.05).Conclusion EMT malignant phenomenon raises cancer stem cells ,which can lead to the development of malignant cells poorly differentiated trends ,they are not an isolated process;important role in the development of EMT and CD 44 +/CD24 -union occurs in non -small cell lung cancer and prognosis with patients ,which provides a potential breakthrough in the treatment of cancer prevention and treatment targets .