Background::Type 2 diabetes (T2D), but not type 1, protected against amyotrophic lateral sclerosis (ALS). In T2D serum insulin is normal or elevated in the early stages. Type 1 diabetes, characterized by a total lack of insulin, is associated with an increased risk of ALS. The antidiabetic metformin also protects against ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open channel via which toxic substances from astrocytes reach motor neurons to cause ALS.Methods::In the current study we analyzed FDA MedWatch data to determine whether insulin or metformin could reduce the risk of ALS. We performed in silico molecular docking studies and molecular dynamics simulation with Cx43 to determine if insulin or metformin dock within the Cx43 channel and can block it effectively, again reducing risk of ALS.Results::In MedWatch, Insulin use is associated with a significantly reduced risk of ALS (Proportional Reporting Ratio 0.401). Metformin use is associated with a significantly reduced risk of ALS (PRR 0.567). The Human insulin heterodimer docked within center of the Cx43 channel, effectively blocking it. Molecular dynamics simulation showed that the block is highly stable and may be responsible for the protective effect of T2D on ALS. Metformin docks within the Cx43 channel, but the relatively small size of the metformin molecule may not allow it to obstruct the passage of toxic substances from astrocytes to motor neurons.Conclusion::MedWatch data indicate that both insulin and metformin reduce risk of ALS. The results of our in silico docking study and molecular dynamics simulation corroborate our previous findings with Cx31. Insulin docks within the open hemichannel of hexameric Cx43, potentially blocking it. Molecular dynamics simulation showed that the block is stable and may be responsible for the protective effect of T2D and insulin on ALS.

Background::Type 2 diabetes (T2D), but not type 1, protected against amyotrophic lateral sclerosis (ALS). In T2D serum insulin is normal or elevated in the early stages. Type 1 diabetes, characterized by a total lack of insulin, is associated with an increased risk of ALS. The antidiabetic metformin also protects against ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open channel via which toxic substances from astrocytes reach motor neurons to cause ALS.Methods::In the current study we analyzed FDA MedWatch data to determine whether insulin or metformin could reduce the risk of ALS. We performed in silico molecular docking studies and molecular dynamics simulation with Cx43 to determine if insulin or metformin dock within the Cx43 channel and can block it effectively, again reducing risk of ALS.Results::In MedWatch, Insulin use is associated with a significantly reduced risk of ALS (Proportional Reporting Ratio 0.401). Metformin use is associated with a significantly reduced risk of ALS (PRR 0.567). The Human insulin heterodimer docked within center of the Cx43 channel, effectively blocking it. Molecular dynamics simulation showed that the block is highly stable and may be responsible for the protective effect of T2D on ALS. Metformin docks within the Cx43 channel, but the relatively small size of the metformin molecule may not allow it to obstruct the passage of toxic substances from astrocytes to motor neurons.Conclusion::MedWatch data indicate that both insulin and metformin reduce risk of ALS. The results of our in silico docking study and molecular dynamics simulation corroborate our previous findings with Cx31. Insulin docks within the open hemichannel of hexameric Cx43, potentially blocking it. Molecular dynamics simulation showed that the block is stable and may be responsible for the protective effect of T2D and insulin on ALS.

BACKGROUND: Venous thromboembolism is a common complication in patients with glioma. The clotting factor von Willebrand factor (VWF) is a highly adhesive procoagulant molecule that mediates platelet adhesion to endothelial and subendothelial surfaces. In the current analysis, we examined The Cancer Genome Atlas (TCGA) data to assess the VWF gene in patients with lower grade gliomas. METHODS: For newly diagnosed gliomas, we evaluated the association between VWF and overall survival in the Genomic Data Commons TCGA Lower Grade Glioma (LGG) dataset in TCGA. Simple statistics were calculated to identify patterns of mutual exclusivity or co-occurrence of VWF mutations. For each pair of query genes an odds ratio was calculated that indicates the likelihood that the mutations in the two genes are mutually exclusive or co-occurrent across the selected cases. To determine whether the identified relationship was significant for a gene pair, Fisher's exact test was performed. RESULTS: Lower grade gliomas with less VWF gene expression had significantly better survival than those with more VWF gene expression (hazard ratio 0.64, 95% confidence interval 0.44 to 0.92, p=0.015 log rank test). When we analyzed the data with Cox regression, VWF expression had a significant effect on survival (p=0.02) that was unrelated to the effect of IDH1 expression (p=0.062), TP53 expression (p=0.135), independent of ATRX expression (p=0.021) and histology (astrocytoma versus oligoastrocytoma and oligodendroglioma, p=0.002). VWF mutations significantly co-occur with mutations in TP53 and ATRX (p<0.001). CONCLUSION: The deleterious prognostic effect of VWF expression and its co-occurrent mutations with TP53 and ATRX in lower grade gliomas are not surprising, given VWF's role in other cancers. Therefore, VWF gene expression may be a clinically important risk marker in lower grade glioma.
Adhesives ; Blood Platelets ; Dataset ; Gene Expression ; Genes, vif ; Genome ; Glioblastoma ; Glioma ; Humans ; Odds Ratio ; Oligodendroglioma ; Venous Thromboembolism ; von Willebrand Factor