Cortactin mediates elevated shear stress-induced mucin hypersecretion via actin polymerization in human airway epithelial cells

Mucus hypersecretion is a remarkable pathophysiological manifestation in airway obstructive diseases. These diseases are usually accompanied with elevated shear stress due to bronchoconstriction. Previous studies have reported that shear stress induces mucin5AC (MUC5AC) secretion via actin polymerization in cultured nasal epithelial cells. Furthermore, it is well known that cortactin, an actin binding protein, is a central mediator of actin polymerization. Therefore, we hypothesized that cortactin participates in MUC5AC hypersecretion induced by elevated shear stress via actin polymerization in cultured human airway epithelial cells. Compared with the relevant control groups, Src phosphorylation, cortactin phosphorylation, actin polymerization and MUC5AC secretion were significantly increased after exposure to elevated shear stress. Similar effects were found when pretreating the cells with jasplakinolide, and transfecting with wild-type cortactin. However, these effects were significantly attenuated by pretreating with Src inhibitor, cytochalasin D or transfecting cells with the specific small interfering RNA of cortactin. Collectively, these results suggest that elevated shear stress induces MUC5AC hypersecretion via tyrosine-phosphorylated cortactin-associated actin polymerization in cultured human airway epithelial cells.     

Matrix metalloproteinase (MMP)-2 and MMP-9 polymorphisms and haplotypes as disease biomarkers

Chaudhary and colleagues observed associations of matrix metalloproteinase (MMP)-2 (-1306C/T) and MMP-9 (-1562C/T) promoter polymorphisms with head and neck squamous cell carcinoma (HNSCC), but not with oral submucous fibrosis (OSMF) in an Indian population. We suggest that they could carry out a haplotype analysis with their data on MMP-2 genotypes (-1306C/T and -168G/T) and that they consider genotyping the microsatellite -90 (CA)_14–24 in the MMP-9 promoter region in order to perform haplotype analysis in combination with their data on MMP-9 (-1562C/T) polymorphism. These suggestions could provide additional information with clinical relevance to cancer susceptibility.     

Interferon Induced IFIT Family Genes in Host Antiviral Defense

Secretion of interferons (IFNs) from virus-infected cells is a hallmark of host antiviral immunity and in fact, IFNs exert their antiviral activities through the induction of antiviral proteins. The IFN-induced protein with tetratricopeptide repeats (IFITs) family is among hundreds of IFN-stimulated genes. This family contains a cluster of duplicated loci. Most mammals have IFIT1, IFIT2, IFIT3 and IFIT5; however, bird, marsupial, frog and fish have only IFIT5. Regardless of species, IFIT5 is always adjacent to SLC16A12. IFIT family genes are predominantly induced by type I and type III interferons and are regulated by the pattern recognition and the JAK-STAT signaling pathway. IFIT family proteins are involved in many processes in response to viral infection. However, some viruses can escape the antiviral functions of the IFIT family by suppressing IFIT family genes expression or methylation of 5'' cap of viral molecules. In addition, the variants of IFIT family genes could significantly influence the outcome of hepatitis C virus (HCV) therapy. We believe that our current review provides a comprehensive picture for the community to understand the structure and function of IFIT family genes in response to pathogens in human, as well as in animals.     

Glycosaminoglycans in infectious disease

Glycosaminoglycans (GAGs) are complex carbohydrates that are ubiquitously present on the cell surface and in the extracellular matrix. Interactions between GAGs and pathogens represent the first line of contact between pathogen and host cell and are crucial to a pathogen's invasive potential. Their complexity and structural diversity allow GAGs to control a wide array of biological interactions influencing many physiological and pathological processes, including adhesion, cell‐to‐cell communication, biochemical cascades, and the immune response. In recent years, increasing evidence indicates an extraordinary role for GAGs in the pathogenesis of viruses, bacteria and parasites. Herein, we examine the interface between GAGs and different pathogens, and address the divergent biological functions of GAGs in infectious disease. We consider approaches to use this understanding to design novel therapeutic strategies addressing new challenges in the treatment of infectious diseases.     

Pulmonary embolism and 3-month outcomes in 4036 patients with venous thromboembolism and chronic obstructive pulmonary disease: data from the RIETE registry

Background

Patients with chronic obstructive pulmonary disease (COPD) have a modified clinical presentation of venous thromboembolism (VTE) but also a worse prognosis than non-COPD patients with VTE. As it may induce therapeutic modifications, we evaluated the influence of the initial VTE presentation on the 3-month outcomes in COPD patients.

Methods

COPD patients included in the on-going world-wide RIETE Registry were studied. The rate of pulmonary embolism (PE), major bleeding and death during the first 3 months in COPD patients were compared according to their initial clinical presentation (acute PE or deep vein thrombosis (DVT)).

Results

Of the 4036 COPD patients included, 2452 (61%; 95% CI: 59.2-62.3) initially presented with PE. PE as the first VTE recurrence occurred in 116 patients, major bleeding in 101 patients and mortality in 443 patients (Fatal PE: first cause of death). Multivariate analysis confirmed that presenting with PE was associated with higher risk of VTE recurrence as PE (OR, 2.04; 95% CI: 1.11-3.72) and higher risk of fatal PE (OR, 7.77; 95% CI: 2.92-15.7).

Conclusions

COPD patients presenting with PE have an increased risk for PE recurrences and fatal PE compared with those presenting with DVT alone. More efficient therapy is needed in this subtype of patients.     

Toward an integrative view of Optineurin functions

This review highlights recent advances in our understanding of the mechanisms of Optineurin (Optn) action and its implication in diseases. Optn has emerged as a key player regulating various physiological processes, including membrane trafficking, protein secretion, cell division and host defense against pathogens. Furthermore, there is growing evidence for an association of Optn mutations with human diseases such as primary open-angle glaucoma, amyotrophic lateral sclerosis and Paget’s disease of bone. Optn functions depend on its precise subcellular localization and its interaction with other proteins. Here, we review the mechanisms that allow Optn to ensure a timely and spatially coordinated integration of different physiological processes and discuss how their deregulation may lead to different pathologies.     

The primary cilium

The primary cilium is an antenna-like organelle that plays a vital role in organ generation and maintenance. It protrudes from the cell surface where it receives signals from the surrounding environment and relays them into the cell. These signals are then integrated to give the required outputs in terms of proliferation, differentiation, migration and polarization that ultimately lead to organ development and homeostasis. Defects in cilia function underlie a wide range of diverse but related human developmental or degenerative diseases. Collectively known as ciliopathies, these disorders present with varying severity and multiple organ involvement. The appreciation of the medical importance of the primary cilium has stimulated a huge effort into studies of the underlying cellular mechanisms. These in turn have revealed that ciliopathies result not only from defective assembly or organization of the primary cilium, but also from impaired ciliary signaling. This special edition of Organogenesis contains a set of review articles that highlight the role of the primary cilium in organ development and homeostasis, much of which has been learnt from studies of the associated human diseases. Here, we provide an introductory overview of our current understanding of the structure and function of the cilium, with a focus on the signaling pathways that are coordinated by primary cilia to ensure proper organ generation and maintenance.     

How independent are TSE agents from their hosts?

Central to understanding the nature TSE agents (or prions) is how their genetic information is distinguished from the host. Are TSEs truly infectious diseases with host-independent genomes, or are they aberrations of a host component derived from the host genome? Recent experiments tested whether glycosylation of host PrP affects TSE strain characteristics. Wild-type mice were infected with 3 TSE strains passaged through transgenic mice with PrP devoid of glycans at 1 or both N-glycosylation sites. Strain-specific characteristics of 1 TSE strain changed but did not change for 2 others. Changes resulted from the selection of mutant TSE strains in a novel replicative environment. In general the properties of established TSEs support the genetic independence of TSE agents from the host, and specifically the primary structure of PrP does not directly encode TSE agent properties. However sporadic TSEs, challenge this independency. The prion hypothesis explains emerging TSEs relatively successfully but poorly accounts for the diversity and mutability of established TSE strains, or how many different infectious conformations are sustained thermodynamically. Research on early changes in RNA expression and events at the ribosome may inform the debate on TSE agent properties and their interaction with host cell machinery.     

TRPM7 and its role in neurodegenerative diseases

Calcium (Ca²⁺) and magnesium (Mg²⁺) ions have been shown to play an important role in regulating various neuronal functions. In the present review we focus on the emerging role of transient potential melastatin-7 (TRPM7) channel in not only regulating Ca²⁺ and Mg²⁺ homeostasis necessary for biological functions, but also how alterations in TRPM7 function/expression could induce neurodegeneration. Although eight TRPM channels have been identified, the channel properties, mode of activation, and physiological responses of various TRPM channels are quite distinct. Among the known 8 TRPM channels only TRPM6 and TRPM7 channels are highly permeable to both Ca²⁺ and Mg²⁺; however here we will only focus on TRPM7 as unlike TRPM6, TRPM7 channels are abundantly expressed in neuronal cells. Importantly, the discrepancy in TRPM7 channel function and expression leads to various neuronal diseases such as Alzheimer disease (AD) and Parkinson disease (PD). Further, it is emerging as a key factor in anoxic neuronal death and in other neurodegenerative disorders. Thus, by understanding the precise involvement of the TRPM7 channels in different neurodegenerative diseases and by understanding the factors that regulate TRPM7 channels, we could uncover new strategies in the future that could evolve as new drug therapeutic targets for effective treatment of these neurodegenerative diseases.