Discovery of Novel Oxazepine Derivatives as Akt/ROCK Inhibitors for Growth Arrest and Differentiation Induction in Neuroblastoma Treatment

Patients with high-risk neuroblastoma face limited treatment choices, typically involving a combination of cytotoxic and differentiation maintenance therapies due to a scarcity of drugs. Evidence suggests that targeted inhibitors may provide opportunities for inducing neuroblastoma differentiation while inhibiting proliferation. Here, we demonstrate the synergistic effect of inhibiting Akt and ROCK in antineuroblastoma and present the design and discovery of a new Akt/ROCK inhibitor, B12. It displays strong antiproliferative effects and excellent differentiation inducing activity against Neuro2a cells. Treatment with B12 results in the arrest of G0/G1 cell cycles, a significant decrease in N-myc protein level, and an increase in differentiation markers. The administration of B12 effectively suppresses xenograft tumor growth and promotes differentiation. Overall, the discovery of B12 based on the Akt/ROCK dual inhibition strategy may provide hope for the development of more effective and targeted therapies for this challenging disease

Discovery of Novel Oxazepine Derivatives as Akt/ROCK Inhibitors for Growth Arrest and Differentiation Induction in Neuroblastoma Treatment

Patients with high-risk neuroblastoma face limited treatment choices, typically involving a combination of cytotoxic and differentiation maintenance therapies due to a scarcity of drugs. Evidence suggests that targeted inhibitors may provide opportunities for inducing neuroblastoma differentiation while inhibiting proliferation. Here, we demonstrate the synergistic effect of inhibiting Akt and ROCK in antineuroblastoma and present the design and discovery of a new Akt/ROCK inhibitor, B12. It displays strong antiproliferative effects and excellent differentiation inducing activity against Neuro2a cells. Treatment with B12 results in the arrest of G0/G1 cell cycles, a significant decrease in N-myc protein level, and an increase in differentiation markers. The administration of B12 effectively suppresses xenograft tumor growth and promotes differentiation. Overall, the discovery of B12 based on the Akt/ROCK dual inhibition strategy may provide hope for the development of more effective and targeted therapies for this challenging disease

Discovery of Novel Oxazepine Derivatives as Akt/ROCK Inhibitors for Growth Arrest and Differentiation Induction in Neuroblastoma Treatment

Patients with high-risk neuroblastoma face limited treatment choices, typically involving a combination of cytotoxic and differentiation maintenance therapies due to a scarcity of drugs. Evidence suggests that targeted inhibitors may provide opportunities for inducing neuroblastoma differentiation while inhibiting proliferation. Here, we demonstrate the synergistic effect of inhibiting Akt and ROCK in antineuroblastoma and present the design and discovery of a new Akt/ROCK inhibitor, B12. It displays strong antiproliferative effects and excellent differentiation inducing activity against Neuro2a cells. Treatment with B12 results in the arrest of G0/G1 cell cycles, a significant decrease in N-myc protein level, and an increase in differentiation markers. The administration of B12 effectively suppresses xenograft tumor growth and promotes differentiation. Overall, the discovery of B12 based on the Akt/ROCK dual inhibition strategy may provide hope for the development of more effective and targeted therapies for this challenging disease

Discovery of Novel Oxazepine Derivatives as Akt/ROCK Inhibitors for Growth Arrest and Differentiation Induction in Neuroblastoma Treatment

Patients with high-risk neuroblastoma face limited treatment choices, typically involving a combination of cytotoxic and differentiation maintenance therapies due to a scarcity of drugs. Evidence suggests that targeted inhibitors may provide opportunities for inducing neuroblastoma differentiation while inhibiting proliferation. Here, we demonstrate the synergistic effect of inhibiting Akt and ROCK in antineuroblastoma and present the design and discovery of a new Akt/ROCK inhibitor, B12. It displays strong antiproliferative effects and excellent differentiation inducing activity against Neuro2a cells. Treatment with B12 results in the arrest of G0/G1 cell cycles, a significant decrease in N-myc protein level, and an increase in differentiation markers. The administration of B12 effectively suppresses xenograft tumor growth and promotes differentiation. Overall, the discovery of B12 based on the Akt/ROCK dual inhibition strategy may provide hope for the development of more effective and targeted therapies for this challenging disease

Discovery of Novel Oxazepine Derivatives as Akt/ROCK Inhibitors for Growth Arrest and Differentiation Induction in Neuroblastoma Treatment

Patients with high-risk neuroblastoma face limited treatment choices, typically involving a combination of cytotoxic and differentiation maintenance therapies due to a scarcity of drugs. Evidence suggests that targeted inhibitors may provide opportunities for inducing neuroblastoma differentiation while inhibiting proliferation. Here, we demonstrate the synergistic effect of inhibiting Akt and ROCK in antineuroblastoma and present the design and discovery of a new Akt/ROCK inhibitor, B12. It displays strong antiproliferative effects and excellent differentiation inducing activity against Neuro2a cells. Treatment with B12 results in the arrest of G0/G1 cell cycles, a significant decrease in N-myc protein level, and an increase in differentiation markers. The administration of B12 effectively suppresses xenograft tumor growth and promotes differentiation. Overall, the discovery of B12 based on the Akt/ROCK dual inhibition strategy may provide hope for the development of more effective and targeted therapies for this challenging disease

Image1_Association of methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C>T) gene polymorphism with ischemic stroke risk in different populations: An updated meta-analysis.TIF

Background: Recently, increasing evidence has implicated methylenetetrahydrofolate reductase (MTHFR) gene mutation as a risk factor for ischemic stroke (IS) in the general population. However, studies have been inconclusive and lack evidence on specific populations. We aim to determine whether the rs1801133 (NC_000001.11 (MTHFR):g. 677C>T (p.Ala222Val) variant, we termed as MTHFR rs1801133 (677 C>T), is linked to an increased risk of IS in different age groups and ancestry groups.Methods: The literature relevant to our study was found by searching the PubMed, Cochrane Library, Web of Science, EMBASE, and CNKI databases. A random effect model analysis was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate any possible association. We conducted a subgroup analysis based on the age and ancestry groups of the included populations.Results: As of March 2022, 1,925 citations had been identified in electronic databases, of which 96 studies involving 34,814 subjects met our eligibility criteria. A strong link was found between IS and the MTHFR gene rs1801133 (677C>T) polymorphism in all genetic models [dominant genetic model (OR = 1.47; 95%CI = 1.33–1.61; p T) variant may increase the risk of IS in Asian, Hispanic, or Latin population, middle-aged, and elderly populations (p Conclusion: Our results implied that mutation of the T allele of MTHFR rs1801133 (677C>T) could be a risk factor for IS. A significant association was found among Asian, Hispanic, or Latin population, middle-aged, and elderly people.</p