Bidirectional interaction of airway epithelial remodeling and inflammation in asthma.

Asthma is a chronic disease of the airways that has long been viewed predominately as an inflammatory condition. Accordingly, current therapeutic interventions focus primarily on resolving inflammation. However, the mainstay of asthma therapy neither fully improves lung function nor prevents disease exacerbations, suggesting involvement of other factors.

Cigarette smoke downregulates Nur77 to exacerbate inflammation in chronic obstructive pulmonary disease (COPD).

Cigarette smoke (CS) contains multiple gaseous and particulate materials that can cause lung inflammation, and smoking is the major cause of chronic obstructive pulmonary disease (COPD). We sought to determine the mechanisms of how CS triggers lung inflammation. Nur77, a nuclear hormone receptor belonging to the immediate-early response gene family, controls inflammatory responses, mainly by suppressing the NF-κB signaling pathway.

Glucocorticoid Receptor α Mediates Roflumilast's Ability to Restore Dexamethasone Sensitivity in COPD.

Background: Glucocorticoids are commonly prescribed to treat inflammation of the respiratory system; however, they are mostly ineffective for controlling chronic obstructive pulmonary disease (COPD)-associated inflammation. This study aimed to elucidate the molecular mechanisms responsible for such glucocorticoid inefficacy in COPD, which may be instrumental to providing better patient outcomes. Roflumilast is a selective phosphodiesterase-4 (PDE4) inhibitor with anti-inflammatory properties in severe COPD patients who have a history of exacerbations.

Molecular, chemical, and structural characterization of prostaglandin A2 as a novel agonist for Nur77.

Nur77 is a transcription factor belonging to the NR4A subfamily of nuclear hormone receptors. Upon induction, Nur77 modulates the expression of its target genes and controls a variety of biological and pathophysiological processes. Prior research that revealed a structurally atypical ligand-binding domain (LBD) and failed to locate an endogenous ligand had led to a classification of Nur77 as an orphan receptor.

Key Functions and Therapeutic Prospects of Nur77 in Inflammation Related Lung Diseases.

The transcription factor Nur77 belongs to the NR4A subfamily of nuclear hormone receptors. It features an atypical ligand-binding site that precludes canonical ligand binding, leading to the designation orphan nuclear receptor. However, recent studies show that small molecules can interact with the receptor and modulate its activity by inducing a conformational change in the Nur77 ligand-binding site.

Identification and Molecular Characterization of Peroxisome Proliferator-Activated Receptor δ as a Novel Target for Covalent Modification by 15-Deoxy-Δ-prostaglandin J.

PPARδ belongs to the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors. Upon activation by an agonist, PPARδ controls a variety of physiological processes via regulation of its target genes. 15-Deoxy-Δ-prostaglandin J (15d-PGJ) is a cyclopentenone prostaglandin that features an electrophilic, α,β-unsaturated ketone (an enone) in the cyclopentenone ring.

Role of GPx3 in PPARγ-induced protection against COPD-associated oxidative stress.

Cigarette smoke, a source of numerous oxidants, produces oxidative stress and exaggerated inflammatory responses that lead to irreversible lung tissue damage. It is the single, most significant risk factor for chronic obstructive pulmonary disease (COPD). Although an intrinsic defense system that includes both enzymatic and non-enzymatic modulators exists to protect lung tissues against oxidative stress, impairment of these protective mechanisms has been demonstrated in smokers and COPD patients.

Airway Epithelial Cell Peroxisome Proliferator-Activated Receptor γ Regulates Inflammation and Mucin Expression in Allergic Airway Disease.

Airway epithelial cells (AECs) orchestrate inflammatory responses to airborne irritants that enter the respiratory system. A viscous mucus layer produced by goblet cells in the airway epithelium also contributes to a physiological defense mechanism through the physical and chemical barriers it provides. Dysregulation or impairment in these functions has been implicated as a cause of the chronic inflammation and tissue remodeling that constitute major pathological features of asthma.

PPARs: Key Regulators of Airway Inflammation and Potential Therapeutic Targets in Asthma.

Asthma affects approximately 300 million people worldwide, significantly impacting quality of life and healthcare costs. While current therapies are effective in controlling many patients' symptoms, a large number continue to experience exacerbations or treatment-related adverse effects. Alternative therapies are thus urgently needed.

PPAR Agonists for the Prevention and Treatment of Lung Cancer.

Lung cancer is the most common and most fatal of all malignancies worldwide. Furthermore, with more than half of all lung cancer patients presenting with distant metastases at the time of initial diagnosis, the overall prognosis for the disease is poor. There is thus a desperate need for new prevention and treatment strategies.

Downregulation of 26S proteasome catalytic activity promotes epithelial-mesenchymal transition.

The epithelial-mesenchymal transition (EMT) endows carcinoma cells with phenotypic plasticity that can facilitate the formation of cancer stem cells (CSCs) and contribute to the metastatic cascade. While there is substantial support for the role of EMT in driving cancer cell dissemination, less is known about the intracellular molecular mechanisms that govern formation of CSCs via EMT. Here we show that β2 and β5 proteasome subunit activity is downregulated during EMT in immortalized human mammary epithelial cells.

Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency.

The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome.

Kindlins, integrin activation and the regulation of talin recruitment to αIIbβ3.

Talins and kindlins bind to the integrin β3 cytoplasmic tail and both are required for effective activation of integrin αIIbβ3 and resulting high-affinity ligand binding in platelets. However, binding of the talin head domain alone to β3 is sufficient to activate purified integrin αIIbβ3 in vitro. Since talin is localized to the cytoplasm of unstimulated platelets, its re-localization to the plasma membrane and to the integrin is required for activation.

Subcellular localization of talin is regulated by inter-domain interactions.

Talin, which is composed of head (THD) and rod domains, plays an important role in cell adhesion events in diverse species including most metazoans and Dictyostelium discoideum. Talin is abundant in the cytosol; however, it mediates adhesion by associating with integrins in the plasma membrane where it forms a primary link between integrins and the actin cytoskeleton. Cells modulate the partitioning of talin between the plasma membrane and the cytosol to control cell adhesion.

BCR-ABL-transformed GMP as myeloid leukemic stem cells.

During blast crisis of chronic myelogenous leukemia (CML), abnormal granulocyte macrophage progenitors (GMP) with nuclear beta-catenin acquire self-renewal potential and may function as leukemic stem cells (Jamieson et al. N Engl J Med, 2004). To develop a mouse model for CML-initiating GMP, we expressed p210(BCR-ABL) in an established line of E2A-knockout mouse BM cells that retain pluripotency in ex vivo culture.

Integrin activation.

Agonist stimulation of integrin receptors, composed of transmembrane alpha and beta subunits, leads cells to regulate integrin affinity ('activation'), a process that controls cell adhesion and migration, and extracellular matrix assembly. A final step in integrin activation is the binding of talin to integrin beta cytoplasmic domains. We used forward, reverse and synthetic genetics to engineer and order integrin activation pathways of a prototypic integrin, platelet alphaIIbbeta3.

Characterization of R-ras3/m-ras null mice reveals a potential role in trophic factor signaling.

R-Ras3/M-Ras is a member of the RAS superfamily of small-molecular-weight GTP-binding proteins. Previous studies have demonstrated high levels of expression in several regions of the central nervous system, and a constitutively active form of M-Ras promotes cytoskeletal reorganization, cellular transformation, survival, and differentiation. However, the physiological functions of M-Ras during embryogenesis and postnatal development have not been elucidated.

Targeted inhibition of the KLF6 splice variant, KLF6 SV1, suppresses prostate cancer cell growth and spread.

Prostate cancer is a leading cause of cancer death in men. Risk prognostication, treatment stratification, and the development of rational therapeutic strategies lag because the molecular mechanisms underlying the initiation and progression from primary to metastatic disease are unknown. Multiple lines of evidence now suggest that KLF6 is a key prostate cancer tumor suppressor gene including loss and/or mutation in prostate cancer tumors and cell lines and decreased KLF6 expression levels in recurrent prostate cancer samples.

Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6.

The Kruppel-like transcription factor KLF6 is a novel tumor-suppressor gene mutated in a significant fraction of human prostate cancer. It is localized to human chromosome 10p14-15, a region that displays frequent loss of heterozygosity in glioblastoma multiforme (GBM). Indeed, mutations of the KLF6 gene have recently been reported in this tumor type.