Butyrate suppresses expression of neuropilin I in colorectal cell lines through inhibition of Sp1 transactivation

Background: Neuropilin is a transmembrane receptor for vascular endothelial growth factor (VEGF) and is expressed in normal endothelial cells and upregulated in cancer cells. Neuropilin-1 (NRP-1) has been shown to promote tumour cell migration and survival in colon cancer in response to VEGF binding. The expression profiles of neuropilins, associated co-receptors and known ligands have been mapped in three colorectal cell lines: Caco-2, HCT116 & HT29. We have previously shown that butyrate, a naturally occurring histone deacetylase inhibitor (HDACi) produced by fermentation of fibre in the colon, causes apoptosis of colon cancer cell lines. Results: Here we demonstrate that butyrate down-regulates NRP-1 and VEGF at the mRNA and protein level in colorectal cancer cell lines. NRP-1 is a known transcriptional target of Sp1, whose activity is regulated by acetylation. NRP-1 down-regulation by butyrate was associated with decreased binding affinity of Sp1 for canonical Sp-binding sites in the NRP-1 promoter. siRNA-mediated knock-down of Sp1 implied that Sp1 may have strong DNA binding activity but weak transactivation potential. Conclusion: The downregulation of the key apoptotic and angiogenesis regulator NRP-1 by butyrate suggests a novel contributory mechanism to the chemopreventive effect of dietary fibre

Transforming growth factor-beta and endoglin signaling orchestrate wound healing

Physiological wound healing is a complex process requiring the temporal and spatial co-ordination of various signaling networks, biomechanical forces, and biochemical signaling pathways in both hypoxic and non-hypoxic conditions. Although a plethora of factors are required for successful physiological tissue repair, transforming growth factor beta (TGF-β) expression has been demonstrated throughout wound healing and shown to regulate many processes involved in tissue repair, including production of ECM, proteases, protease inhibitors, migration, chemotaxis, and proliferation of macrophages, fibroblasts of the granulation tissue, epithelial and capillary endothelial cells. TGF-β mediates these effects by stimulating signaling pathways through a receptor complex which contains Endoglin. Endoglin is expressed in a broad spectrum of proliferating and stem cells with elevated expression during hypoxia, and regulates important cellular functions such as proliferation and adhesion via Smad signaling. This review focuses on how the TGF-β family and Endoglin, regulate stem cell availability, and modulate cellular behavior within the wound microenvironment, includes current knowledge of the signaling pathways involved, and explores how this information may be applicable to inflammatory and/or angiogenic diseases such as fibrosis, rheumatoid arthritis and metastatic cancer

Fibrinogen E fragment selectively disrupts the vasculature and inhibits the growth of tumours in a syngeneic murine model

We recently demonstrated that a fragment of human fibrinogen, fibrinogen E fragment, inhibits the migration and differentiation of human endothelial cells in vitro. Here we show that it exerts similar effects on murine endothelial cells in vitro, and selectively disrupts tumour endothelium in vivo, causing widespread intravascular thrombosis and retarding the growth of CT26 tumours in a syngeneic murine model

Bevacizumab resistance in breast cancer: are neuropilins the key?

During breast cancer growth and development, angiogenesis is triggered by the interaction between vascular endothelial growth factor (VEGF) and its receptors VEGF-R1 and VEGF-R2. In breast cancer, alternative VEGF receptors, the neuropilins (Np1 and Np2), are often upregulated and serve to augment the effects of VEGF-R1/VEGF-R2 binding and provide alternative signalling pathways. Recently, a humanized antibody, Bevacizumab (Bz), which prevents VEGF binding to VEGF-R1/VEGF-R2, in combination with chemotherapy demonstrated initial efficacy (increased progression-free survival) in breast cancer phase III clinical trials. Eventually, however, the tumours evade treatment control. This may be because neuropilins are not blocked by Bz and provide an alternative VEGF signalling pathway in breast cancer. Therefore the present study aims to evaluate the potential of enhancing efficacy of Bz treatment by simultaneously blocking VEGF–neuropilin binding

High road utilizers surveys compared to police data for road traffic crash hotspot localization in Rwanda and Sri Lanka

10.1186/s12889-015-2609-1BMC Public Health1615

Possible evidence for intraspecific aggression in a pliocene crocodile from north Queensland

A large, fossilised crocodilian metatarsal has been recovered from the Pliocene Bluff Downs Local Fauna exhibiting proliferative bone growth consistent with an episode of osteoperiostitis, possibly resulting from trauma. The nature and location of this trauma suggests that it may have occurred as a result of intraspecific aggression between rival animals. Three crocodilian genera have been recovered from the Fluff Downs Fauna, Crocodylus, Quinkana and Pallimnarchus. The metatarsal does not conform to Crocodylus porosus and therefore most probably represents one of the other two known crocodilian taxa The nature of the injury suggests that it occurred in water and it may belong to the now extinct Plio-Pleistocene Pallimnarchus rather than Quinkana babarra which is interpreted as being predominantly terrestrial