1,413 research outputs found
Steps towards collective sustainability in biomedical research
The optimism surrounding multistakeholder research initiatives does not match the clear view of policies that are needed to exploit the potential of these collaborations. Here we propose some action items that stem from the integration between research advancements with the perspectives of patient-advocacy organizations, academia, and industry
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Periodontitis-induced systemic inflammation exacerbates atherosclerosis partly via endothelial-mesenchymal transition in mice.
Growing evidence suggests close associations between periodontitis and atherosclerosis. To further understand the pathological relationships of these associations, we developed periodontitis with ligature placement around maxillary molars or ligature placement in conjunction with Porphyromonas gingivalis lipopolysaccharide injection at the ligature sites (ligature/P.g. LPS) in Apolipoprotein E knock out mice and studied the atherogenesis process in these animals. The mice were fed with high fat diet for 11 weeks and sacrificed for analyzing periodontitis, systemic inflammation, and atherosclerosis. Controls did not develop periodontitis or systemic inflammation and had minimal lipid deposition in the aortas, but mice receiving ligature or ligature/P.g. LPS showed severe periodontitis, systemic inflammation, and aortic plaque formation. The aortic plaque contained abundant macrophages and cells expressing both endothelial and mesenchymal cell markers. The severity of periodontitis was slightly higher in mice receiving ligature/P.g. LPS than ligature alone, and the magnitude of systemic inflammation and aortic plaque formation were also notably greater in the mice with ligature/P.g. LPS. These observations indicate that the development of atherosclerosis is due to systemic inflammation caused by severe periodontitis. In vitro, P.g. LPS enhanced the secretion of pro-inflammatory cytokines from macrophages and increased the adhesion of monocytes to endothelial cells by upregulating the expression of adhesion molecules from endothelial cells. Moreover, secretory proteins, such as TNF-α, from macrophages induced endothelial-mesenchymal transitions of the endothelial cells. Taken together, systemic inflammation induced by severe periodontitis might exacerbate atherosclerosis via, in part, causing aberrant functions of vascular endothelial cells and the activation of macrophages in mice
Ischemia and reperfusion injury in kidney transplantation : relevant mechanisms in injury and repair
Ischemia and reperfusion injury (IRI) is a complex pathophysiological phenomenon, inevitable in kidney transplantation and one of the most important mechanisms for non- or delayed function immediately after transplantation. Long term, it is associated with acute rejection and chronic graft dysfunction due to interstitial fibrosis and tubular atrophy. Recently, more insight has been gained in the underlying molecular pathways and signalling cascades involved, which opens the door to new therapeutic opportunities aiming to reduce IRI and improve graft survival. This review systemically discusses the specific molecular pathways involved in the pathophysiology of IRI and highlights new therapeutic strategies targeting these pathways
MicroRNA-148b Targets the TGF-β Pathway to Regulate Angiogenesis and Endothelial-to-Mesenchymal Transition during Skin Wound Healing
Transforming growth factor beta (TGF-β) is crucial for regulation of the endothelial cell (EC) homeostasis. Perturbation of TGF-β signaling leads to pathological conditions in the vasculature, causing cardiovascular disease and fibrotic disorders. The TGF-β pathway is critical in endothelial-to-mesenchymal transition (EndMT), but a gap remains in our understanding of the regulation of TGF-β and related signaling in the endothelium. This study applied a gain- and loss-of function approach and an in vivo model of skin wound healing to demonstrate that miR-148b regulates TGF-β signaling and has a key role in EndMT, targeting TGFB2 and SMAD2. Overexpression of miR-148b increased EC migration, proliferation, and angiogenesis, whereas its inhibition promoted EndMT. Cytokine challenge decreased miR-148b levels in ECs while promoting EndMT through the regulation of SMAD2. Finally, in a mouse model of skin wound healing, delivery of miR-148b mimics promoted wound vascularization and accelerated closure. In contrast, inhibition of miR-148b enhanced EndMT in wounds, resulting in impaired wound closure that was reversed by SMAD2 silencing. Together, these results demonstrate for the first time that miR-148b is a key factor controlling EndMT and vascularization. This opens new avenues for therapeutic application of miR-148b in vascular and tissue repair
Regulation of endothelial cell plasticity by TGF-β
Recent evidence has demonstrated that endothelial cells can have a remarkable plasticity. By a process called Endothelial-to-Mesenchymal Transition (EndMT) endothelial cells convert to a more mesenchymal cell type that can give rise to cells such as fibroblasts, but also bone cells. EndMT is essential during embryonic development and tissue regeneration. Interestingly, it also plays a role in pathological conditions like fibrosis of organs such as the heart and kidney. In addition, EndMT contributes to the generation of cancer associated fibroblasts that are known to influence the tumor-microenvironment favorable for the tumor cells. EndMT is a form of the more widely known and studied Epithelial-to-Mesenchymal Transition (EMT). Like EMT, EndMT can be induced by transforming growth factor (TGF)-β. Indeed many studies have pointed to the important role of TGF-β receptor/Smad signaling and downstream targets, such as Snail transcriptional repressor in EndMT. By selective targeting of TGF-β receptor signaling pathological EndMT may be inhibited for the therapeutic benefit of patients with cancer and fibrosis
Akt promotes Endocardial-Mesenchyme Transition
Endothelial to mesenchyme transition (EndMT) can be observed during the formation of endocardial cushions from the endocardium, the endothelial lining of the atrioventricular canal (AVC), of the developing heart at embryonic day 9.5 (E9.5). Many regulators of the process have been identified; however, the mechanisms driving the initial commitment decision of endothelial cells to EndMT have been difficult to separate from processes required for mesenchymal proliferation and migration. We have several lines of evidence that suggest a central role for Akt signaling in committing endothelial cells to enter EndMT. Akt1 mRNA was restricted to the endocardium of endocardial cushions while they were forming. The PI3K/Akt signaling pathway is necessary for mesenchyme outgrowth, as sprouting was inhibited in AVC explant cultures treated with the PI3K inhibitor LY294002. Furthermore, endothelial marker, VE-cadherin, was downregulated and mesenchyme markers, N-cadherin and Snail, were induced in response to expression of a constitutively active form of Akt1 (myrAkt1) in endothelial cells. Finally, we isolated the function of Akt1 signaling in the commitment to the transition using a transgenic model where myrAkt1 was pulsed only in endocardial cells and turned off after EndMT initiation. In this way, we determined that increased Akt signaling in the endocardium drives EndMT and discounted its other functions in cushion mesenchymal cells
Non-coding RNA in Endothelial-to-Mesenchymal Transition
Endothelial-to-mesenchymal transition (EndMT) is the process wherein endothelial cells lose their typical endothelial cell markers and functions and adopt a mesenchymal-like phenotype. EndMT is required for development of the cardiac valves, the pulmonary and dorsal aorta and arterial maturation, but activation of the EndMT program during adulthood is believed to contribute to several pathologies including organ fibrosis, cardiovascular disease and cancer. Non-coding RNAs, including microRNAs, long non-coding RNAs and circular RNAs, modulate EndMT during development and disease. Here, we review the mechanisms by which non-coding RNAs facilitate or inhibit EndMT during development and disease and provide a perspective on the therapeutic application of non-coding RNAs to treat fibroproliferative cardiovascular disease
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