Click Chemistry of Melamine Dendrimers: Comparison of "Click-and-Grow" and "Grow-Then-Click" Strategies Using a Divergent Route to Diversity.

Dendrimers are attractive macromolecules for a broad range of applications owing to their well-defined shapes and dimensions, highly branched and globular architectures, and opportunities for exploiting multivalency. Triazine dendrimers in particular offer advantages such as ease of synthesis, stability, well-defined spherical structure, multivalency, potential to achieve acceptable drug loadings, and low polydispersity. In this study, the potential utility of alkyne-azide "click" cycloadditions of first-, second-, and third-generation triazine dendrimers containing three or six alkynyl groups with benzyl azide was examined using copper catalysts. "Click-and-grow" and "grow-then-click" strategies were employed. For the first- and second- generation dendrimers, the desired triazole derivatives were obtained in high yields and purified by simple reprecipitation without column chromatography; however, some difficulties were observed in the preparation of third-generation dendrimers. The desired reaction proceeded under microwave irradiation as well as with simple heating. This click chemistry can be utilized for various melamine dendrimers that are fabricated with other amine linkers.

The potential of GPNMB as novel neuroprotective factor in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease characterized by the loss of motor neurons. Despite substantial research, the causes of ALS remain unclear. Glycoprotein nonmetastatic melanoma protein B (GPNMB) was identified as an ALS-related factor using DNA microarray analysis with mutant superoxide dismutase (SOD1(G93A)) mice. GPNMB was greatly induced in the spinal cords of ALS patients and a mouse model as the disease progressed. It was especially expressed in motor neurons and astrocytes. In an NSC34 cell line, glycosylation of GPNMB was inhibited by interaction with SOD1(G93A), increasing motor neuron vulnerability, whereas extracellular fragments of GPNMB secreted from activated astrocytes attenuated the neurotoxicity of SOD1(G93A) in neural cells. Furthermore, GPNMB expression was substantial in the sera of sporadic ALS patients than that of other diseased patients. This study suggests that GPNMB can be a target for therapeutic intervention for suppressing motor neuron degeneration in ALS.

Apoptosis-inducing factor and cyclophilin A cotranslocate to the motor neuronal nuclei in amyotrophic lateral sclerosis model mice.

AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease whose mechanism is not understood. Recently, it was reported that apoptosis-inducing factor (AIF) was involved in motor neuronal cell death in ALS model mice, and AIF-induced neuronal cell death by interacting with cyclophilin A (CypA). However, it is unknown whether the CypA and AIF-complex induces chromatinolysis in ALS. Therefore, in the present study, we investigated the process of motor neuron degeneration as the disease progresses and to determine whether the CypA-AIF complex would play a role in inducing motor neuronal cell death in mutant superoxide dismutase 1 (SOD1)(G93A) ALS model mice. METHODOLOGY: We prepared the nuclear fractions of spinal cords and demonstrated the nuclear translocation of CypA with AIF in SOD1(G93A) mice by immunoprecipitation. The localization of CypA and AIF in the spinal cords was assessed by immunohistochemistry. RESULTS: In the spinal cords of SOD1(G93A) mice, the expressions of CypA and AIF were detected in the motor neurons, and CypA and AIF cotranslocated to the motor neuronal nuclei with CypA. Furthermore, the expression of CypA was detected in GFAP-positive astrocytes, but not in CD11b-positive microglial cells. On the other hand, these findings were not detected in the spinal cords of wild-type mice. CONCLUSIONS: From these results, we suggest that CypA and AIF may play cooperative and pivotal roles in motor neuronal death in the murine ALS model.