Neurogenesis and angiogenesis are two important processes that may contribute to the repair of brain injury after stroke. This study was designed to investigate whether transplantation of human embryonic neural stem cells (NSCs) into cortical peri-infarction 24h after ischemia effects cell proliferation in the subventricular zone (SVZ) and angiogenesis in the peri-infarct zone. NSCs were prepared from embryonic human brains at 8 weeks gestation. Focal cerebral ischemia was induced by permanent occlusion of the middle cerebral artery of adult rats. Animals were randomly divided into two groups (n=30, each) at 24h after ischemia: NSC-grafted and medium-grafted groups. Toluidine blue staining and 5'-bromo-2'-deoxyuridine (BrdU) or von Willebrand factor (vWF) immunohistochemistry were performed at 7, 14 and 28 days after transplantation. NSC transplantation increased the number of BrdU-positive cells in the ischemic ipsilateral SVZ compared with the medium control at 7 days (P<0.01). This difference in SVZ cell proliferation persisted at 14 days (P<0.01), but was not significant at 28 days (P>0.05). In addition, angiogenesis, as indicated by BrdU and vWF staining in cortical peri-infarct regions, was augmented by 46% and 65% in NSC-grafted rats versus medium-grafted rats at 7 and 14 days, respectively (P<0.05). However, this increase became non-significant at 28 days (P>0.05). Our results indicate that NSC transplantation enhances endogenous cell proliferation in the SVZ and promotes angiogenesis in the peri-infarct zone, even if it is performed in the acute phase of ischemic injury.

As alternatives to small-molecular proteolysis-targeting chimeras (PROTAC), peptide-based molecular glues (MG) are a broad range of dual-functional ligands that simultaneously bind with targetable proteins and E3 ligases by mimicking proteinprotein interaction (PPI) partners. Methods: Herein, we design a peptide-derived MG to target a tumor-driving protein, MDMX, for degradation, and nanoengineered it into a supramolecular gold(I)-thiol-peptide complex (Nano-MP) to implement the proteolysis recalcitrance, cellular internalization, and glutathione-triggered release. To optimize the tumor targeting, a pH-responsive macromolecule termed polyacryl sulfydryl imidazole (PSI) was synthesized to coat Nano-MP. Results: As expected, Nano-MP@PSI induced the MDMX degradation by ubiquitination and subsequently restored the anti-cancer function of p53 and p73. Nano-MP@PSI revealed potent anti-cancer activities in an orthotopic xenograft mouse model of retinoblastoma by intraocular injection and a patient-derived xenograft model of malignant pancreatic cancer by systemic injection, while maintaining a favorable safety profile and showing a highly favorable clearable profile of excretion from the living body. Conclusion: Collectively, this work not only provided a clinically viable paradigm for the treatment of a wide variety of tumors by multiple administration types, but, more importantly, it bridged the chasm between peptides and PROTACs, and likely reinvigorated the development of peptide-derived proteolysis-targeting chimeras for a great variety of diseases.

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The results indicate that NSC transplantation has anti-apoptotic activity and can improve the neurological function; these effects are mediated by the up-regulation of Bcl-2 expression in the penumbra.

Transplantation of stem cells is a potential therapeutic strategy for stroke damage. The survival, migration, and differentiation of transplanted human embryonic neural stem cells in the acute post-ischemic environment were characterized and endogenous nestin expression after transplantation was investigated. Human embryonic neural stem cells obtained from the temporal lobe cortex were cultured and labeled with fluorescent 1,1'-dioctadecy-6,6'-di (4-sulfopheyl)-3,3,3',3'-tetramethylindocarbocyanin (DiI) in vitro. Labeled cells were transplanted into cortical peri-infarction zones of adult rats 24 h after permanent middle cerebral artery occlusion. Survival, migration, and differentiation of grafted cells were quantified in immunofluorescence-stained sections from rats sacrificed at 7, 14, and 28 days after transplantation. Endogenous nestin-positive cells in the cortical peri-infarction zone were counted at serial time points. The cells transplanted into the cortical peri-infarction zone displayed the morphology of living cells and became widely located around the ischemic area. Moreover, some of the transplanted cells expressed nestin, GFAP, or NeuN in the peri-infarction zone. Furthermore, compared with the control group, endogenous nestin-positive cells in the peri-infarction zone had increased significantly 7 days after cell transplantation. These results confirm the survival, migration, and differentiation of transplanted cells in the acute post-ischemic environment and enhanced endogenous nestin expression within a brief time window. These findings indicate that transplantation of neural stem cells into the peri-infarction zone may be performed as early as 24 h after ischemia.