Development of drugs targeting Bcl-2 relatives and caspases, for treating diseases including cancer and inflammatory disorders, often involves measuring interactions with recombinant target molecules, and/or monitoring cancer cell killing in vitro. Here, we present yeast-based methods for evaluating drug-mediated inhibition of Bcl-2 relatives or caspases. Active Bax and caspases kill Saccharomyces cerevisiae, and pro-survival Bcl-2 proteins can inhibit Bax-induced yeast death. By measuring the growth or adenosine triphosphate content of transformants co-expressing Bax with pro-survival Bcl-2 relatives, we found that the Bcl-2 antagonist drugs ABT-737 or ABT-263 abolished Bcl-2 or Bcl-xL function and reduced Bcl-w activity, but failed to inhibit Mcl-1, A1 or the poxvirus orthologs DPV022 and SPPV14. Using this technique, we also demonstrated that adenoviral E1B19K was resistant to these agents. The caspase inhibitor Q-VD-OPh suppressed yeast death induced by caspases 1 and 3. Yeast engineered to express human apoptotic regulators enable simple, automatable assessment of the activity and specificity of candidate drugs targeting Bcl-2 relatives or caspases.
Neuroblastoma (NB) is one of the most common heterogeneous extracranial cancers in infancy that arises from neural crest (NC) cells of the sympathetic nervous system. The Wnt signaling pathway, both canonical and noncanonical pathway, is a highly conserved signaling pathway that regulates the development and differentiation of the NC cells during embryogenesis. Reports suggest that aberrant activation of Wnt ligands/receptors in Wnt signaling pathways promote progression and relapse of NB. Wnt signaling pathways regulate NC induction and migration in a similar manner; it regulates proliferation and metastasis of NB. Inhibiting the Wnt signaling pathway or its ligands/receptors induces apoptosis and abrogates proliferation and tumorigenicity in all major types of NB cells. Here, we comprehensively discuss the Wnt signaling pathway and its mechanisms in regulating the development of NC and NB pathogenesis. This review highlights the implications of aberrant Wnt signaling in the context of etiology, progression, and relapse of NB. We have also described emerging strategies for Wnt‐based therapies against the progression of NB that will provide new insights into the development of Wnt‐based therapeutic strategies for NB.
Senecio gracili orus DC root extract was studied for secondary metabolite composition following bioactivity guided isolation technique. The ethyl acetate extract of Senecio gracili orus root yielded nine chemical constituents: 3,4-di-tert-butyl toluene, stigmasterol, β-sitosterol, 2β-(angeloyloxy)furanoeremophilane, gallic acid, 2β-{[(Z)-2-hydroxymethylbut-2enoyl]oxy}furanoeremophilane,1-Hydroxypentan-2-yl-4-methylbenzoate, sarcinnic acid, and sitosterol 3-Oβ-D-glucopyranoside. The structures of the chemical constituents were elucidated on the basis of spectral data analysis in the light of literature. All the compounds are being reported for the rst time from this plant. The isolated constituents were screened for in-vitro neuroprotective effects against corticostereone induced impairment. Among various isolated compounds, three natural products (sarcinnic acid, gallic acid and β-sitosterol) displayed robust neurotropic activity. These three compounds increased neuronal cell survival in differentiated neuroblastoma cells from high dose corticosterone (400µM) induced cell death. The studies are aimed to explore small molecules for treating neurodegeneration underlying various neurological disorders to restore neuronal cell plasticity.
DeclarationsAcknowledgement: The authors (Showkat Ahmad Bhat and Loveleena Kaur) are thankful to CSIR and DST respectively for providing fellowship support.Ethical approval: The work was reviewed and approved by institutional ethics and publication committee. The committee has assigned CSIR-IIIM/IPR/00291 as the research paper number.
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