Evaluation of the Safety and Toxicity of the Original Copper Nanocomposite Based on Poly-N-vinylimidazole

A new original copper nanocomposite based on poly-N-vinylimidazole was synthesized and characterized by a complex of modern physicochemical and biological methods. The low cytotoxicity of the copper nanocomposite in relation to the cultured hepatocyte cells was found. The possibility to involve the copper from the nanocomposite in the functioning of the copper-dependent enzyme systems was evaluated during the incubation of the hepatocyte culture with this nanocomposite introduced to the nutrient medium. The synthesized new water-soluble copper-containing nanocomposite is promising for biotechnological and biomedical research as a new non-toxic hydrophilic preparation that is allowed to regulate the work of key enzymes involved in energy metabolism and antioxidant protection as well as potentially serving as an additional source of copper.

ANGPLT3 Impacts Not Only Proteinuria But Also Hyperlipidemia in Nephrotic Syndrome

Background: Why primary nephrotic syndrome (PNS) patients often accompany with dyslipidemia is unknown. Recent studies discovered that angiopoietin-like protein 3 (ANGPTL3) is an important regulator in lipid metabolism. In this study, we explored how ANGPTL3 impact dyslipidemia in PNS development. Methods: We detected the expression serum level of ANGPTL3 in PNS patients. Further, degree of proteinuria and lipid metabolism were tested in angptl3 overexpression-transgenic (angptl3-tg) mice at different weeks of age. Meanwhile, this study used CRISP/Cas 9 system to build angptl3-knockout (angptl3-/-) mice to observe LPS-treated nephrotic mice. Results: There was a significant correlation between the expression level of serum ANGPTL3 and the level of cholesterol, triglyceride and low density lipoprotein in PNS patients. Along with the age growing, the angptl3-tg mice emerged more and more severe hypertriglyceridemia and proteinuria. The pathological features showed rich lipid droplets deposition of hepatocytes and diffuse podocytes effacement with these angptl3-tg mice. Compared to wild type mice, angptl3-/- mice showed significant less degree of lipid dysfunction and proteinuria after treated with LPS. The ANGPTL3’ effects on nephrotic dyslipidemia was confirmed in the cultured hepatocyte with knock-down or overexpressed angptl3. Finally, the significant alters of lipoprotein lipase (LPL) were tested in liver tissues between Angptl3-/- and wild type mice with LPS treatment. Conclusion: ANGPTL3 could be involved in development of dyslipidemia, besides proteinuria in PNS pathogenesis. Inhibiting LPL expression is a reason why ANGPTL3 induce hyperlipidemia in PNS.

ERRATUM

Testing drugs in isogenic rodent strains to satisfy regulatory requirements is insufficient for derisking organ toxicity in genetically diverse human populations; in contrast, advances in mouse genetics can help mitigate these limitations. Compared to the expensive and slower in vivo testing, in vitro cultures enable the testing of large compound libraries toward prioritizing lead compounds and selecting an animal model with human-like response to a compound. In the case of the liver, a leading cause of drug attrition, isolated primary mouse hepatocytes (PMHs) rapidly decline in function within current culture platforms, which restricts their use for assessing the effects of longer-term compound exposure. Here we addressed this challenge by fabricating mouse micropatterned cocultures (mMPCC) containing PMHs and 3T3-J2 murine embryonic fibroblasts that displayed 4 weeks of functions; mMPCCs created from either C57Bl/6J or CD-1 PMHs outperformed collagen/Matrigel™ sandwich-cultured hepatocyte monocultures by ∼143-fold, 413-fold, and 10-fold for albumin secretion, urea synthesis, and cytochrome P450 activities, respectively. Such functional longevity of mMPCCs enabled in vivo relevant comparisons across strains for CYP induction and hepatotoxicity following exposure to 14 compounds with subsequent comparison to responses in primary human hepatocytes (PHHs). In conclusion, mMPCCs display high levels of major liver functions for several weeks and can be used to assess strain- and species-specific compound effects when used in conjunction with responses in PHHs. Ultimately, mMPCCs can be used to leverage the power of mouse genetics for characterizing subpopulations sensitive to compounds, characterizing the degree of interindividual variability, and elucidating genetic determinants of severe hepatotoxicity in humans.