https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

Molecular mechanisms of epithelial–mesenchymal transition

For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

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The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer

To get to the site of inflammation, leukocytes must first adhere to and traverse the blood-vessel wall, events that occur in a cascade-like manner. But what are the exact steps in this cascade and what molecules are involved?

Getting to the site of inflammation: the leukocyte adhesion cascade updated

physiological implications (ERM) proteins: activation mechanisms and Osmotic cell shrinkage activates ezrin/radixin/moesin

Tissue accumulation of contractile myofibroblasts is a key feature of a multitude of fibrotic diseases. Myofibroblast generation either from epithelial or mesenchymal precursors involves the activation of a myogenic program, hallmarked by the expression of α-smooth muscle actin (SMA). Recent research suggests that this robust phenotypic reprogramming requires two critical inputs: the fibrogenic cytokine transforming growth factor-β1 (TGFβ) and an injury (or absence) of intercellular junctions. This two-hit paradigm of epithelial-myofibroblast transition (EMyT) postulates that the injured (contact-deprived) epithelium is locally and selectively sensitive (topically susceptible) to the transforming effect of TGFβ, while the intact areas are quite resistant to the phenotype-changing effect of this cytokine. Searching for molecular mechanisms underlying the synergy between contact injury and TGFβ, we found that an interplay among three multifunctional transcriptional (co)activators, the junction component β-catenin, the TGFβ receptor target Smad3, and the actin cytoskeleton-regulated myocardin-related transcription factor (MRTF) controls the magnitude and timing of SMA expression.1 Moreover, this regulation is realized not only at the transcriptional level. Notably, these factors form a pretranscriptional circuit, in which they impact each other’s activity and stability. Based on this recent paper we ponder about the mechanisms of cellular plasticity in the context of EMyT. We propose that topical susceptibility to TGFβ, triggered by cell contact-modulated pretranscriptional and transcriptional control is realized through the crosstalk of a few master regulators, whose coordinated action tailors SMA expression and contributes to the major decision of whether injury leads to healing or fibrosis.

How do your contacts (or their absence) shape your fate

Tissue fibrosis manifests as excessive deposition of compacted, highly aligned collagen fibrils, which interfere with organ structure and function. Cells in collagen‐rich lesions often exhibit marked overexpression of discoidin domain receptor 1 (DDR1), which is linked to increased collagen compaction through the association of DDR1 with the Ca2+‐dependent nonmuscle myosin IIA (NMIIA). We examined the functional relationship between DDR1 and the transient receptor potential vanilloid type 4 (TRPV4) channel, a Ca2+‐permeable ion channel that is implicated in collagen compaction. Fibroblasts expressing high levels of DDR1 were used to model cells in lesions with collagen compaction. In these cells, the expression of the β1 integrin was deleted to simplify studies of DDR1 function. Compared with DDR1 wild‐type cells, high DDR1 expression was associated with increased Ca2+ influx through TRPV4, enrichment of TRPV4 in collagen adhesions, and enhanced contractile activity mediated by NMIIA. At cell adhesion sites to collagen, DDR1 associated with TRPV4, which enhanced DDR1‐mediated collagen alignment and compaction. We conclude that DDR1 regulates Ca2+ influx through the TRPV4 channel to promote critical, DDR1‐mediated processes that are important in lesions with collagen compaction and alignment.

DDR1 associates with TRPV4 in cell‐matrix adhesions to enable calcium‐regulated myosin activity and collagen compaction

Ever since Thomas Kuhn’s brilliant postulate that scientific progress is generated in the context of paradigms (commonly accepted notions), and that scientific revolutions manifest as paradigm shifts, we not only work along paradigms but are striving to consciously create them. Moreover, paradigms emerge not only within science but also about science, i.e., paradigms about how science should be done and how it should interact with society. In our field, the currently reigning paradigm (or more properly perhaps meta-paradigm or zeitgeist) is undoubtedly that of knowledge translation. Indeed, knowledge translation (KT) is a crucially important concept. And yet when a paradigm or rather its application becomes a self-imposed dogma or an overbearing cliche, it may counteract progress.

When one receives criticism that one’s work is “cutting edge research in an enigmatic area in cell biology but the explanation how it is translational to clinic is weak,” one starts pondering the zeitgeist that compels referees to assess everything from the KT angle. And during such pondering over the current state of affairs, it suddenly dawned on me that the very concept of knowledge translation as it is applied today, is fundamentally—philosophically—flawed. In fact, it is a misnomer. What is being forced on us is not knowledge translation but science translation. And of course, knowledge and science are not the same. Far from it. Let me explain.

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A little (up)SET THEORY: a philosophical and psychological pondering of a scientist on the state of our art.

Delayed neutrophil (pmn) apoptosis is associated with increased mitochondrial membrane potential and preservation of cytochrome c in experimental and clinical sepsis.

Andras Kapus

Papers

physiological implications (ERM) proteins: activation mechanisms and Osmotic cell shrinkage activates ezrin/radixin/moesin

How do your contacts (or their absence) shape your fate

DDR1 associates with TRPV4 in cell‐matrix adhesions to enable calcium‐regulated myosin activity and collagen compaction

A little (up)SET THEORY: a philosophical and psychological pondering of a scientist on the state of our art.

Delayed neutrophil (pmn) apoptosis is associated with increased mitochondrial membrane potential and preservation of cytochrome c in experimental and clinical sepsis.