chir-99021 and Neurodegenerative-Diseases

Glycogen synthase kinase 3β (GSK-3β) is involved in a variety of diseases such as neurodegenerative diseases, bipolar disorder, and diabetes. In this study, a series of heterobifunctional small molecule proteolysis targeting chimera (PROTAC) were designed and synthesized based on E3 ubiquitin ligase cereblon (CRBN). Most of PROTACs displayed good inhibitory activity, with the IC

Topics: Animals; Enzyme Inhibitors; Glycogen Synthase Kinase 3 beta; HT29 Cells; Humans; Models, Molecular; Neurodegenerative Diseases; PC12 Cells; Proteolysis; Rats; Small Molecule Libraries

No effective treatment is currently available for neurodegenerative diseases, and existing pharmacotherapy is inconsistent with severe side effects. Cell replacement therapy is promising for neurodegenerative disease treatment, and the induction of neurons is an unmet need for such therapy. The present study investigated the potential of a combined medium composed of conditioned medium and eight small molecular compounds in reprogramming human foreskin fibroblasts (HFFs) into neurons. HFFs were cultured from foreskin and then induced by small molecules to generate neurons. The results demonstrated that the conditioned medium containing forskolin, RepSox, SP600125, CHIR99021, Go6983, Y‑27632, IXS9 and I‑BET151 effectively induced human fibroblasts to change into neurons in vitro. Following a 30‑day induction, the cells exhibited neuronal properties as determined by morphological and phenotypical alterations. The induced cells exhibited expression of neuronal markers, including class III β‑tubulin, microtubule‑associated protein 2, vesicular glutamate transporter 1 and γ‑aminobutyric acid, accompanied by increased expression of neuronal transcription factors, including neuronal differentiation 1 and achaete‑scute family bHLH transcription factor 1, and decreased expression levels of fibroblast‑specific genes. Furthermore, these cells also exhibited electrophysiological properties of neurons. Notably, the course of cell morphological alterations demonstrated the differentiation of fibroblasts into neurons. The present study provided a novel combination of existing small molecular compounds that efficiently reprogramed human fibroblasts into neurons.

Topics: Amides; Anthracenes; Cell Differentiation; Cells, Cultured; Cellular Reprogramming; Cellular Reprogramming Techniques; Colforsin; Culture Media, Conditioned; Fibroblasts; Foreskin; Humans; Indoles; Male; Maleimides; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Pyrazoles; Pyridines; Pyrimidines; Transcription Factors

Although significant progress in understanding brain function has been made in the last 15 years, the unmet medical need for effective therapeutic treatment of devastating neurodegenerative disorders is still enormous and represents a formidable challenge at the beginning of the 21st century. With the recent accumulation of evidence that the Wnt signaling pathway might be impaired in such diseases, a new avenue for potential therapeutic intervention has been opened which comprises many putative drug targets.

Topics: Animals; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Homeostasis; Humans; Indoles; Lithium Chloride; Maleimides; Models, Biological; Nervous System; Neurodegenerative Diseases; Pyridines; Pyrimidines; Signal Transduction; Thiazoles; Urea; Wnt Proteins