Derived Growth Factor Receptor Research Articles

C-KIT inhibitors reduce pathology and improve behavior in the Tg(SwDI) model of Alzheimer's disease.

Treatments for Alzheimer's disease have primarily focused on removing brain amyloid plaques to improve cognitive outcomes in patients. We developed small compounds, known as BK40143 and BK40197, and we hypothesize that these drugs alleviate microglial-mediated neuroinflammation and induce autophagic clearance of neurotoxic proteins to improve behavior in models of neurodegeneration. Specificity binding assays of BK40143 and BK40197 showed primary binding to c-KIT/Platelet Derived Growth Factor Receptors (PDGFR)α/β, whereas BK40197 also differentially binds to FYVE finger-containing phosphoinositide kinase (PIKFYVE). Both compounds penetrate the CNS, and treatment with these drugs inhibited the maturation of peripheral mast cells in transgenic mice, correlating with cognitive improvements on measures of memory and anxiety. In the brain, microglial activation was profoundly attenuated and amyloid-beta and tau were reduced via autophagy. Multi-kinase inhibition, including c-KIT, exerts multifunctional effects to reduce neurodegenerative pathology via autophagy and microglial activity and may represent a potential therapeutic option for neurodegeneration.

Telocytes as potential targets in a cyclophosphamide-induced animal model of premature ovarian failure.

Premature ovarian failure (POF) refers to the presence of ovarian atrophic permanent amenorrhea in women under the age of 40. The pathogenesis of POF remains to be fully elucidated. Telocytes are a group of specialized cells with a small cell volume and very long cytoplasmic prolongations with dichotomous branching. Previous studies have indicated that telocytes function to support the trachea and serve as stem cell niches. Although it has been confirmed that telocytes are present in numerous organs in mammals, it remains to be determined whether they are present in ovarian tissues and whether they are involved in the development of POF. The present study used a cyclophosphamide-induced mouse model of POF. Hematoxylin and eosin staining and an enzyme-linked immunosorbent assay revealed that cyclophosphamide induced edema and apoptosis of ovarian stromal and granulosa cells and increased atretic follicles. In addition, cyclophosphamide induced abnormal peripheral blood FSH and E2 levels in mice. Transmission electron microscopy revealed a small number of telocyte-like cell structures in the ovarian stroma of wild-type mice. In addition, flow cytometry and immunohistochemical staining results suggested that the number of cluster of differentiation (CD)34/platelet-derived growth factor receptor (PDGFR)α, CD34/PDGFRβ and CD34/vimentin double-positive cells in the ovaries of POF mice was significantly decreased compared with wild-type mice. In conclusion, mouse ovarian tissues appear to contain telocytes, and cyclophosphamide treatment significantly reduced the number of ovarian telocytes. Therefore, telocytes may serve as a potential novel marker of POF induced by cyclophosphamide.

Nobiletin Induces Oligodendrocyte Lineage Precursor Cells in a Cuprizone-Administered Demyelination Animal Model

We investigated the effect of nobiletin on the oligodendroglial cell lineage in a cuprizone-induced demyelination animal model. Nobiletin, a polymethoxyflavone, was administered to the model animal for 3 consecutive weeks (50 mg/kg, intraperitoneally, 2 times/week). Immunohistochemical analysis of the corpus callosum and/or Western blotting analysis of brain extracts revealed that cuprizone administration reduced immunoreactivity for myelin-basic protein (MBP), a marker for mature oligodendrocytes, and increased immunoreactivity for platelet derived-growth factor receptor (PDGFR)-α, a marker for oligodendrocyte precursor cells (OPCs). Nobiletin treatment did not affect these changes in the cuprizone-fed mice. Nobiletin treatment, however, increased the immunoreactivity against proteolipid protein (PLP)/DM-20, a marker for mature oligodendrocytes, OPCs, and oligodendrocyte lineage precursor cells, and also augmented immunoreactivity against oligodendrocyte transcription factor 2 (olig2), a marker for OPCs and their precursor cells. These findings suggest that nobiletin promotes the production of oligodendrocyte lineage precursor cells in a demyelination animal model, and that nobiletin treatment might be suitable for individuals with demyelination diseases such as multiple sclerosis.

Tanshinone IIA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization

BackgroundPromotion of endothelial normalization restores tumor oxygenation and obstructs tumor cells invasion, intravasation, and metastasis. We therefore investigated whether a vasoactive drug, tanshinone IIA, could inhibit metastasis by inducing vascular normalization after palliative resection (PR) of hepatocellular carcinoma (HCC).MethodsA liver orthotopic double-tumor xenograft model in nude mouse was established by implantation of HCCLM3 (high metastatic potential) and HepG2 tumor cells. After removal of one tumor by PR, the effects of tanshinone IIA administration on metastasis, tumor vascularization, and survival were evaluated. Tube formation was examined in mouse tumor-derived endothelial cells (TECs) treated with tanshinone IIA.ResultsPR significantly accelerated residual hepatoma metastases. Tanshinone IIA did not inhibit growth of single-xenotransplanted tumors, but it did reduce the occurrence of metastases. Moreover, it inhibited PR-enhanced metastases and, more importantly, prolonged host survival. Tanshinone IIA alleviated residual tumor hypoxia and suppressed epithelial-mesenchymal transition (EMT) in vivo; however, it did not downregulate hypoxia-inducible factor 1α (HIF-1α) or reverse EMT of tumor cells under hypoxic conditions in vitro. Tanshinone IIA directly strengthened tube formation of TECs, associated with vascular endothelial cell growth factor receptor 1/platelet derived growth factor receptor (VEGFR1/PDGFR) upregulation. Although the microvessel density (MVD) of residual tumor tissue increased after PR, the microvessel integrity (MVI) was still low. While tanshinone IIA did not inhibit MVD, it did dramatically increase MVI, leading to vascular normalization.ConclusionsOur results demonstrate that tanshinone IIA can inhibit the enhanced HCC metastasis associated with PR. Inhibition results from promoting VEGFR1/PDGFR-related vascular normalization. This application demonstrates the potential clinical benefit of preventing postsurgical recurrence.

The potential use of tyrosine kinase inhibitors in severe asthma

Severe asthma comprises heterogeneous phenotypes that share in common a poor response to traditional therapies. Recent and ongoing work with tyrosine kinase inhibitors suggests a potential beneficial role in treatment of severe asthma. Various receptor and nonreceptor tyrosine kinase pathways contribute to aspects of airway inflammation, airway hyperresponsiveness, and remodeling of asthma. Selective and nonselective tyrosine kinase inhibitors may be useful to block pathways that are pathologically overactive or overexpressed in severe asthma. Recent in-vivo studies have demonstrated the utility of inhibitors against specific tyrosine kinases (epidermal growth factor receptor, c-kit/platelet derived growth factor receptor, vascular endothelial growth factor receptor, spleen tyrosine kinase, and janus kinase) in altering key aspects of severe asthma. Asthma and even severe asthma does not consist of a single phenotype. Targeting key inflammatory and remodeling pathways engaged across subphenotypes with tyrosine kinase inhibitors appears to hold promise.