Synergistic neurotoxicity of oxygen-glucose deprivation and tetrabromobisphenol A in vitro: role of oxidative stress.

These results suggest the involvement of oxidative stress in the synergistic neurotoxic effects of TBBPA and OGD

Acute Cytotoxicity Evoked by Tetrabromobisphenol A in Primary Cultures of Rat Cerebellar Granule Cells Outweighs the Effects of Polychlorinated Biphenyls

The aim of this study was to identify, among selected environmental toxins, the substance with the highest in vitro toxicity to neurons combined with the most marked induction of calcium imbalance, oxidative stress and mitochondrial dysfunction. Exposure of primary cultures of rat cerebellar granule cells for 30 min to polychlorinated biphenyls (PCBs) or brominated flame retardants (BFRs) at concentrations of 10-50 �M identified tetrabromobisphenol A as the compound with the highest toxicity. At a concentration of 25 �M, apart from the moderate activation of 45Ca uptake, this BFR induced the most pronounced increase in intracellular Ca2+ concentration, depolarization of mitochondria, and activation of ROS productio

Peptide Dendrimers with Non-Symmetric Bola Structure Exert Long Term Effect on Glioblastoma and Neuroblastoma Cell Lines

Background: Glioblastoma (GBM) is the most common malignant tumor of the central nervous system (CNS). Neuroblastoma (NB) is one of the most common cancers of childhood derived from the neural crest cells. The survival rate for patients with GBM and high-risk NB is poor; therefore, novel therapeutic approaches are needed. Increasing evidence suggests a dual role of redox-active compounds in both tumorigenesis and cancer treatment. Therefore, in this study, polyfunctional peptide-based dendrimeric molecules of the bola structure carrying residues with antiproliferative potential on one side and the antioxidant residues on the other side were designed. Methods: We synthesized non-symmetric bola dendrimers and assessed their radical scavenging potency as well as redox capability. The influence of dendrimers on viability of rat primary cerebellar neurons (CGC) and normal human astrocytes (NHA) was determined by propidium iodide staining and cell counting. Cytotoxicity against human GBM cell lines, T98G and LN229, and NB cell line SH-SY5Y was assessed by cell counting and colony forming assay. Results: Testing of CGC and NHA viability allowed to establish a range of optimal dendrimers structure and concentration for further evaluation of their impact on two human GBM and one human NB cell lines. According to ABTS, DPPH, FRAP, and CUPRAC antioxidant tests, the most toxic for normal cells were dendrimers with high charge and an excess of antioxidant residues (Trp and PABA) on both sides of the bola structure. At 5 μM concentration, most of the tested dendrimers neither reduced rat CGC viability below 50–40%, nor harmed human neurons (NHA). The same dose of compounds 16 or 22, after 30 min treatment decreased the number of SH-SY5Y and LN229 cells, but did not affect the number of T98G cells 48 h post treatment. However, either compound significantly reduced the number of colonies formed by SH-SY5Y, LN229, and T98G cells measured 14 days after treatment. Conclusions: Peptide dendrimers with non-symmetric bola structure are excellent scaffolds for design of molecules with pro/antioxidant functionality. Design of molecules with an excess of positive charges and antioxidant residues rendered molecules with high neurotoxicity. Single, 30 min exposition of the GBM and NB cell lines to the selected bola dendrimers significantly suppressed their clonogenic potentia

Molecular Antioxidant Properties and In Vitro Cell Toxicity of the p-Aminobenzoic Acid (PABA) Functionalized Peptide Dendrimers §

Background: Exposure to ozone level and ultraviolet (UV) radiation is one of the major concerns in the context of public health. Numerous studies confirmed that abundant free radicals initiate undesired processes, e.g. carcinogenesis, cells degeneration, etc. Therefore, the design of redox-active molecules with novel structures, containing radical quenchers molecules with novel structures, and understanding their chemistry and biology, might be one of the prospective solutions. Methods: We designed a group of peptide dendrimers carrying multiple copies of p-aminobenzoic acid (PABA) and evaluated their molecular antioxidant properties in 1,1′-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) tests. Cytotoxicity against human melanoma and fibroblast cells as well as against primary cerebral granule cells (CGC) alone and challenged by neurotoxic sodium glutamate and production of reactive oxygen species (ROS) in presence of dendrimers were measured. Results: PABA-terminated dendrimers express enhanced radical and radical cation scavenging properties in relation to PABA alone. In cellular tests, the dendrimers at 100 μM fully suppress and between 20–100 μM reduce proliferation of the human melanoma cell line. In concentration 20 μM dendrimers generate small amount of the reactive oxygen species (<25%) but even in their presence human fibroblast and mouse cerebellar granule cells remain intact Moreover, dendrimers at 0.2–20 µM concentration (except one) increased the percentage of viable fibroblasts and CGC cells treated with 100 μM glutamate. Conclusions: Designed PABA-functionalized peptide dendrimers might be a potential source of new antioxidants with cationic and neutral radicals scavenging potency and/or new compounds with marked selectivity against human melanoma cell or glutamate-stressed CGC neurons. The scavenging level of dendrimers depends strongly on the chemical structure of dendrimer and the presence of other groups that may be prompted into radical form. The present studies found different biological properties for dendrimers constructed from the same chemical fragments but the differing structure of the dendrimer tree provides once again evidence that the structure of dendrimer can have a significant impact on drug–target interactions