A fundamental function of the intestinal epithelium is to act as a barrier that limits interactions between luminal contents such as the intestinal microbiota, the underlying immune system and the remainder of the body, while supporting vectorial transport of nutrients, water and waste products. Epithelial barrier function requires a contiguous layer of cells as well as the junctions that seal the paracellular space between epithelial cells. Compromised intestinal barrier function has been associated with a number of disease states, both intestinal and systemic. Unfortunately, most current clinical data are correlative, making it difficult to separate cause from effect in interpreting the importance of barrier loss. Some data from experimental animal models suggest that compromised epithelial integrity might have a pathogenic role in specific gastrointestinal diseases, but no FDA-approved agents that target the epithelial barrier are presently available. To develop such therapies, a deeper understanding of both disease pathogenesis and mechanisms of barrier regulation must be reached. Here, we review and discuss mechanisms of intestinal barrier loss and the role of intestinal epithelial barrier function in pathogenesis of both intestinal and systemic diseases. We conclude with a discussion of potential strategies to restore the epithelial barrier.

/pdf/the-intestinal-epithelial-barrier-a-therapeutic-target-1g6s473bxs.pdf

The intestinal epithelial barrier: a therapeutic target?

Muscle atrophy frequently complicates the course of chronic kidney disease (CKD) and is associated with excess morbidity and mortality. In this Review, the authors describe how CKD stimulates catabolic pathways that interfere with cellular protein metabolism and discuss how knowledge of these pathways might enable the development of therapies to block muscle wasting in catabolic conditions.

/pdf/mechanisms-of-muscle-wasting-in-chronic-kidney-disease-nu1gkfgcma.pdf

Mechanisms of muscle wasting in chronic kidney disease

Mucosal surfaces are lined by epithelial cells In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste secretion while preventing intrusion by luminal materials Intestinal epithelia therefore play a central role in regulating interactions between the mucosal immune system and luminal contents, which include dietary antigens, a diverse intestinal microbiome, and pathogens The paracellular space is sealed by the tight junction, which is maintained by a complex network of protein interactions Tight junction dysfunction has been linked to a variety of local and systemic diseases Two molecularly and biophysically distinct pathways across the intestinal tight junction are selectively and differentially regulated by inflammatory stimuli This review discusses the mechanisms underlying these events, their impact on disease, and the potential of using these as paradigms for development of tight junction-targeted therapeutic interventions

/pdf/cell-biology-of-tight-junction-barrier-regulation-and-2gd5tqnnte.pdf

Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease

Cell-cell junctions link cells to each other in tissues, and regulate tissue homeostasis in critical cell processes that include tissue barrier function, cell proliferation, and migration. Defects in cell-cell junctions give rise to a wide range of tissue abnormalities that disrupt homeostasis and are common in genetic abnormalities and cancers. Here, we discuss the organization and function of cell-cell junctions primarily involved in adhesion (tight junction, adherens junction, and desmosomes) in two different epithelial tissues: a simple epithelium (intestine) and a stratified epithelium (epidermis). Studies in these tissues reveal similarities and differences in the organization and functions of different cell-cell junctions that meet the requirements for the specialized functions of each tissue. We discuss cell-cell junction responses to genetic and environmental perturbations that provide further insights into their roles in maintaining tissue homeostasis.

/pdf/cell-cell-junctions-organize-structural-and-signaling-3wn0ug2b8y.pdf

Cell-Cell Junctions Organize Structural and Signaling Networks.

Thoracic aortic diseases that involve progressive enlargement, acute dissection, or rupture are influenced by the hemodynamic loads and mechanical properties of the wall. We have only limited understanding, however, of the mechanobiological processes that lead to these potentially lethal conditions. Homeostasis requires that intramural cells sense their local chemomechanical environment and establish, maintain, remodel, or repair the extracellular matrix to provide suitable compliance and yet sufficient strength. Proper sensing, in turn, necessitates both receptors that connect the extracellular matrix to intracellular actomyosin filaments and signaling molecules that transmit the related information to the nucleus. Thoracic aortic aneurysms and dissections are associated with poorly controlled hypertension and mutations in genes for extracellular matrix constituents, membrane receptors, contractile proteins, and associated signaling molecules. This grouping of factors suggests that these thoracic diseases result, in part, from dysfunctional mechanosensing and mechanoregulation of the extracellular matrix by the intramural cells, which leads to a compromised structural integrity of the wall. Thus, improved understanding of the mechanobiology of aortic cells could lead to new therapeutic strategies for thoracic aortic aneurysms and dissections.

Role of Mechanotransduction in Vascular Biology: Focus on Thoracic Aortic Aneurysms and Dissections

http://www.jbc.org/content/289/41/28478.full.pdf

Myosin light chain kinase (MLCK) regulates cell migration in a myosin regulatory light chain phosphorylation-independent mechanism.

Vascular tone, an important determinant of systemic vascular resistance and thus blood pressure, is affected by vascular smooth muscle (VSM) contraction. Key signaling pathways for VSM contraction ...

Role of myosin light chain kinase in regulation of basal blood pressure and maintenance of salt-induced hypertension

Current approaches to generate lentiviral vectors, which have been used extensively for gene therapy, are time consuming and require a large expenditure. Here, we directly clone the full length myosin light chain kinase cDNA into enhanced green fluorescence protein (EGFP)-fused pLenti6/V5 expression vector in just one step with the use of Red-mediated recombination system, allowing for rapid and effective cloning of lentiviral expression vectors. In addition, the simultaneous expression of EGFP reporter provides a convenient monitoring mean for host cell infection and for localization of the target proteins.

One-step construction of lentiviral reporter using Red-mediated recombination.

MiR-23a inhibits myogenic differentiation through down regulation of fast myosin heavy chain isoforms

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Myosin light chain kinase (MLCK) regulates cell migration in a myosin regulatory light chain phosphorylation-independent mechanism.

Role of myosin light chain kinase in regulation of basal blood pressure and maintenance of salt-induced hypertension

One-step construction of lentiviral reporter using Red-mediated recombination.

MiR-23a inhibits myogenic differentiation through down regulation of fast myosin heavy chain isoforms