ABSTRACT
Pyrrolizidine alkaloids (PAs) are a group of hepatic toxicant widely present in plants. Cytochrome P450 (CYP) 3A plays a key role in metabolic activation of PAs to generate electrophilic metabolites, which is the main cause of hepatotoxicity. We have previously demonstrated the sex difference in developmental toxicity and hepatotoxicity in fetal rats exposed to monocrotaline (MCT), a representative toxic PA. The aim of this study was to explore the underlying mechanism. 20â¯mg·kg-1·d-1 MCT was intragastrically given to pregnant Wistar rats from gestation day 9 to 20. CYP3As expression and pregnane X receptor (PXR) activation were specifically enhanced in female fetal liver. After MCT treatment, we also observed a significant increase of CYP3As expression in LO2 cells (high PXR level) or hPXR-transfected HepG2 cells (low PXR level). Employing hPXR and CYP3A4 dual-luciferase reporter gene assay, we confirmed the agonism effect of MCT on PXR-dependent transcriptional activity of CYP3A4. Agonism and antagonism of the androgen receptor (AR) either induced or blocked MCT-induced PXR activation, respectively. This study was the first report identifying that MCT served as PXR agonist to induce CYP3A expression. CYP3A induction may increase self-metabolic activation of MCT and subsequently lead to more severe hepatotoxicity in female fetus. While in male, during the intrauterine period, activated AR by testosterone secretion from developing testes represses MCT-induced PXR activation and CYP3A induction, which may partially protect male fetus from MCT-induced hepatotoxicity.
Subject(s)
Chemical and Drug Induced Liver Injury , Cytochrome P-450 CYP3A/genetics , Liver/drug effects , Monocrotaline/toxicity , Pregnane X Receptor/metabolism , Animals , Cell Line , Chemical and Drug Induced Liver Injury/embryology , Chemical and Drug Induced Liver Injury/genetics , Chemical and Drug Induced Liver Injury/metabolism , Female , Fetal Development/drug effects , Fetus/drug effects , Gene Expression Regulation/drug effects , Humans , Liver/metabolism , Male , Maternal-Fetal Exchange , Pregnancy , Rats, Wistar , Sex CharacteristicsABSTRACT
Riparian zones, the critical ecological interfaces between terrestrial and aquatic ecosystems, are species rich habitats. However, riparian zones are seriously threatened by human activities in the world. Riparian invertebrates represent a large proportion of riparian biodiversity, perform various ecological functions, and provide an essential link between aquatic and terrestrial ecosystems. Although many studies have investigated the riparian invertebrate communities, there is lacking a comprehensive summary of maintaining mechanisms underlying riparian invertebrate diversity. This review discussed seven characteristics of riparian zones that might support high riparian invertebrate diversity: flood and drought, nutrient, microhabitat diversity, riparian vegetation, microclimate gradients, food resources and river spatial gradients. Further, we summarized the maintaining mechanisms of riparian invertebrate diversity. Disturbances of periodic flood and drought trigger the reproduction and migration of invertebrates, increase the turnover of invertebrate communities, and create suitable conditions for riparian invertebrates. Adequate nutrients support a high invertebrate diversity by increasing primary productivity of riparian habitats. Elevated microhabitat diversity provides a variety of niche space for specialist riparian invertebrates. Strong microclimate gradients provide complex and diverse habitats and thus facilitate the coexistence of aquatic and terrestrial invertebrates in riparian zones. Cross-ecosystem resource subsidies increase food availability and contribute unique food sources to riparian invertebrates. The differentiation of these factors along river longitudinal and lateral gradients provides conditions for the diversification of riparian invertebrates at a larger scale. Understanding the maintaining mechanisms of riparian invertebrate diversity is important for conservation of riparian biodiversity and integrated management of river ecosystems.
Subject(s)
Ecosystem , Invertebrates , Animals , Biodiversity , Floods , RiversABSTRACT
Aquaporin 9 (AQP9) is the main aquaglyceroporin in the liver. Few studies have been performed regarding the role of AQP9 in hepatocellular carcinoma (HCC). Here, we report the expression and function of AQP9 in HCC tissues and cell lines. We found that AQP9 mRNA and protein levels were down-regulated in HCC tissues and human hepatoma cell lines compared to the para-cancer normal liver tissues and normal hepatocyte line, respectively. In a human HCC SMMC-7721 cell line, over-expression of AQP9 suppressed cell invasion in vitro and xenograft tumor growth in vivo. AQP9 over-expression increased the expression of E-cadherin and decreased the expression of N-cadherin in SMMC-7721 cells and xenografted tumors, which was correlated with decreased levels of phosphoinositide 3-kinase (PI3K) and p-Akt. Conversely, using siRNA to knock down AQP9 over-expression could reverse the phenotype caused by AQP9 over-expression. Our findings suggest that AQP9 is down-regulated in hepatocellular carcinoma and its over-expression suppresses hepatoma cell invasion through inhibiting epithelial-to-mesenchymal transition.
