Claudins in lung diseases

Tight junctions are the most apically localized part of the epithelial junctional complex. They regulate the permeability and polarity of cell layers and create compartments in cell membranes. Claudins are structural molecules of tight junctions. There are 27 claudins known, and expression of different claudins is responsible for changes in the electrolyte and solute permeability in cells layers. Studies have shown that claudins and tight junctions also protect multicellular organisms from infections and that some infectious agents may use claudins as targets to invade and weaken the host's defense. In neoplastic diseases, claudin expression may be up- or downregulated. Since their expression is associated with specific tumor types or with specific locations of tumors to a certain degree, they can, in a restricted sense, also be used as tumor markers. However, the regulation of claudin expression is complex involving growth factors and integrins, protein kinases, proto-oncogens and transcription factors. In this review, the significance of claudins is discussed in lung disease and development

The NOX toolbox: validating the role of NADPH oxidases in physiology and disease

Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis

Use of an experimental autoimmune model to define nerve growth factor dependency of peripheral and central substance P-containing neurons in the rat

Rats exposed to maternal antibodies against nerve growth factor (NGF) in utero and in milk have been used to investigate the developmental dependency of various substance P-containing neurons on NGF. Substance P and other peptides were measured by radioimmunoassays. The substance P content of sensory ganglia, spinal cord, and skin was depleted 40 to 60% in anti-NGF-treated rats. These results demonstrate the NGF dependence of substance P-containing neurons in sensory ganglia. Opiate binding in the spinal cord was not changed despite the large depletion in substance P: the Bmax and KD were the same in control and treated animals. The results suggest that opiate receptors may not be located presynaptically on substance P-containing primary afferents. Among the peripheral tissues which were assayed (ileum, submaxillary gland, retina, and adrenal), substance P decreased only in the adrenal, suggesting innervation by a NGF-dependent substance P-containing neuron. No changes were detected in the substance P content of nine different brain regions, in agreement with previous observations on the lack of effect of NGF on central neurons.</jats:p

An Individualized Approach to Cancer Screening Decisions in Older Adults: A Multilevel Framework

Guidelines for optimal cancer screening in older adults remain unclear, particularly for adults over the age of 75. While cancer screening in older adults may benefit some in good health, it may cause unnecessary burdens in others with limited life expectancy. Thus, a systematic approach to enable individualized cancer screening decisions in older adults is needed. We suggest a framework that guides such decisions through evidence-based approaches from multiple interactions, and that involves the patient, clinician, and healthcare system. An individualized approach considers differences in disease risk rather than the chronological age of the patient. This paper presents a comprehensive framework that depicts the independent and converging levels of influences on individualized cancer screening decisions in older adults. This Individualized Decisions for Screening (IDS) framework recognizes the reality of these interrelationships, including the tensions that arise when behaviors and outcomes are valued differently at the patient, clinician, and healthcare organization levels. Person-centered approaches are essential to advancing multilevel research of individualized cancer screening decisions among older adults