germanium and Necrosis

Water-soluble germanium nanoparticles (wsGeNPs) with allyamine-conjugated surfaces were fabricated and emit blue fluorescence under ultraviolet light. The wsGeNP was physically and chemically stable at various experimental conditions. Cytotoxicity of the fabricated wsGeNP was examined. MTT assay demonstrated that wsGeNP possessed high toxicity to cells and clonogenic survival assay further indicated that this effect was not resulted from retarding cell growth. Flow cytometric analysis indicated that wsGeNP did not alter the cell cycle profile but the sub-G1 fraction was absent from treated cells. Results from DNA fragmentation and propidium iodide exclusion assays also suggested that apoptotic cell death did not occur in cells treated with wsGeNP. Addition of a necrosis inhibitor, necrostatin-1, attenuated cell damage and indicated that wsGeNP caused necrotic cell death. Cell signaling leads to necrotic death was investigated. Intracellular calcium and reactive oxygen species (ROS) levels were increased upon wsGeNP treatment. These effects can be abrogated by BAPTA-AM and N-acetyl cysteine respectively, resulting in a reduction in cell damage. In addition, wsGeNP caused a decrease in mitochondrial membrane potential (MMP) which could be recovered by cyclosporine A. The cellular signaling events revealed that wsGeNP increase the cellular calcium level which enhances the production of ROS and leads to a reduction of MMP, consequentially results in necrotic cell death.

Topics: Animals; Calcium; Caspase 3; Cell Death; CHO Cells; Cricetinae; Germanium; Membrane Potential, Mitochondrial; Metal Nanoparticles; Necrosis; Reactive Oxygen Species; Signal Transduction; Spectroscopy, Fourier Transform Infrared; Tetrazolium Salts; Thiazoles; Toxicity Tests

Toxicity of single-dose spirogermanium was evaluated after iv and im administration to CDF1 mice and beagle dogs. The im LD50 in mice was approximately threefold greater than the iv LD50. The lethal dose in dogs was the same for both routes of administration, but death was delayed after im injection. Convulsive seizures occurred only after the im doses that were lethal, but they were observed after administration of iv doses that were nonlethal. Microscopic evidence of drug toxicity (necrosis and degeneration) was found in mitotically active tissues: intestinal tract, lymphoid tissue, and bone marrow. Necrosis, hemorrhage, edema, and granulation tissue were observed in the muscle injection site.

Topics: Animals; Bone Marrow; Dogs; Germanium; Injections, Intramuscular; Injections, Intravenous; Intestines; Lethal Dose 50; Lymphoid Tissue; Mice; Necrosis; Organometallic Compounds; Seizures; Spiro Compounds