Αναζήτηση αυτού του ιστολογίου

Δευτέρα 2 Ιανουαρίου 2023

Deferoxamine mesylate enhances mandibular advancement‐induced condylar osteogenesis by promoting H‐type angiogenesis

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Background

The effect of functional orthopedic treatment for mandibular deficiency relies on mandibular advancement (MA)-induced condylar new bone formation. However, this is not easy to achieve, especially in non-growing patients. Therefore, how to obtain reliable MA-induced condylar osteogenesis is much worthy of studying.

Objective

To investigate whether deferoxamine mesylate (DFM) enhances MA-induced condylar osteogenesis in middle-aged mice.

Methods

Forty 30-week-old male C57BL/6J mice were randomly divided into 4 groups: the control (Ctrl), DFM, MA+Ctrl, and MA+DFM groups. After a 4-week experimental period, femurs, tibias, and condyles were collected for morphological, micro-computed tomography, and histological evaluation.

Results

For long bones, DFM reversed osteoporosis in middle-aged mice by promoting H-type angiogenesis. For mandibular condyles, MA promoted condylar osteogenesis in middle-aged mice, thereby allowing the mandible to achieve a stable protruding position. In addition, DFM enhanced the volume and quality of MA-induced condylar new bone formation. Furthermore, histological analysis revealed that DFM enhanced MA-induced condylar subchondral ossification. Mechanistically, it was confirmed that DFM increased the number of H-type vessels and their coupled Osterix+ osteoprogenitors by up-regulating the hypoxia-inducible factor (HIF)-1α signaling pathway, thereby enhancing MA-induced condylar osteogenesis.

Conclusion

Applying DFM to enhance MA-induced condylar osteogenesis through H-type angiogenesis is expected to be an effective strategy to achieve favorable functional orthopedic treatment effectiveness in non-growing patients.
View on Web
στις Δεν υπάρχουν σχόλια:

Small Molecule-mediated Disruption of Ribosome Biogenesis Synergizes With FGFR Inhibitors to Suppress Glioma Cell Growth

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
High-grade gliomas are malignant brain tumors characterized by aggressiveness and resistance to chemotherapy. Prognosis remains dismal, highlighting the need to identify novel molecular dependencies and targets. Ribosome biogenesis (RiBi), taking place in the nucleolus, represents a promising target as several cancer types rely on high RiBi rates to sustain proliferation. Publicly available transcriptomics data of glioma patients revealed a positive correlation between RiBi rates and histological grades. We, therefore, hypothesized that glioma cells could be susceptible to RiBi inhibition.
Methods
Transcriptomics data from glioma patients were analyzed for RiBi-related processes. BMH-21, a small molecule inhibitor of RNA polI transcription, was tested in adult and pediatric high-grade glioma cell lines and a zebrafish transplant model. Cellular phenotypes were evaluated by transcriptomics, cell cycle analysis, and vi ability assays. A chemical synergy screen was performed to identify drugs potentiating BMH-21-mediated effects.
Results
BMH-21 reduced glioma cell viability, induced apoptosis, and impaired the growth of transplanted glioma cells in zebrafish. Combining BMH-21 with TMZ potentiated cytotoxic effects. Moreover, BMH-21 synergized with FGFR inhibitor Erdafitinib, a top hit in the chemical synergy screen. RiBi inhibition using BMH-21, POLR1A siRNA, or Actinomycin D revealed engagement of the FGFR-FGF2 pathway. BMH-21 downregulated FGFR1 and SOX2 levels, whereas FGF2 was induced and released from the nucleolus.
Conclusions
This study conceptualizes the implementation of RiBi inhibition as a viable future therapeutic strategy for glioma and reveals an FGFR connection to the cellular response upon RiBi inhibition with potential translational value.
View on Web
στις Δεν υπάρχουν σχόλια:

Wnt Signaling Regulates MFSD2A-dependent Drug Delivery through Endothelial Transcytosis in Glioma

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed.
Methods
Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient and Mfsd2a EC specific inducible mice were developed to study the underlying molecular mechanisms.
Results
We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MSFD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice.
Conclusions
These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ deli very through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.
View on Web
στις Δεν υπάρχουν σχόλια:
Εγγραφή σε: Αναρτήσεις (Atom)