Intercellular adhesion molecule-1 as a drug target in asthma and rhinitis.

Intercellular adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein receptor of the immunoglobulin superfamily. Endothelial cells, epithelial cells, leukocytes and neutrophils are the major cells expressing ICAM-1. Ligands of ICAM-1 are macrophage adhesion ligand-1, leukocyte function-associated antigen-1 and fibrinogen (extracellular matrix protein). In normal physiological conditions, engagement of ICAM-1 receptor with immunological cells surface ligands assists in homing and trafficking of inflammatory cells to distant tissues. ICAM-1 has also long been known to mediate cell-to-cell interaction during antigen presentation and outside-in cell signalling pathways. ICAM-1-mediated elevated inflammation is implicated in asthma. On respiratory epithelial cells surface, ICAM-1 acts as natural binding site for human rhinovirus (HRV), a common cold virus that ultimately causes exacerbation of asthma. This review presents the findings on the role of ICAM-1 in the complication of asthma and in particular asthma exacerbation by HRV.

Cell signaling molecules as drug targets in lung cancer: an overview.

PURPOSE OF REVIEW: Lung being one of the vital and essential organs in the body, lung cancer is a major cause of mortality in the modern human society. Lung cancer can be broadly subdivided into nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Although NSCLC is sometimes treated with surgery, the advanced and metastatic NSCLC and SCLC usually respond better to chemotherapy and radiation. The most important targets of these chemotherapeutic agents are various intracellular signaling molecules. The primary focus of this review article is to summarize the description of various cell signaling molecules involved in lung cancer development and their regulation by chemotherapeutic agents. RECENT FINDINGS: Extensive research work in recent years has identified several cellular signaling molecules that may be intricately involved in the complexity of lung cancer. Some of these cell signaling molecules are epidermal growth factor receptors, vascular endothelial growth factor receptors, mammalian target of rapamycin, mitogen-activated protein kinase phosphatase-1, peroxisome proliferator-activated receptor-gamma, matrix metalloproteinases and receptor for advanced glycation end-products. SUMMARY: The present review will strengthen our current knowledge regarding the efficacy of the above-mentioned cell signaling molecules as potential beneficial drug targets against lung cancer.

Role of estrogen receptors in pro-oxidative and anti-oxidative actions of estrogens: a perspective.

BACKGROUND: Estrogens are steroid hormones responsible for the primary and secondary sexual characteristics in females. While pre-menopausal women use estrogens as the main constituents of contraceptive pills, post-menopausal women use the same for Hormone Replacement Therapy. Estrogens produce reactive oxygen species by increasing mitochondrial activity and redox cycling of estrogen metabolites. The phenolic hydroxyl group present at the C3 position of the A ring of estrogens can get oxidized either by accepting an electron or by losing a proton. Thus, estrogens might act as pro-oxidant in some settings, resulting in complicated non-communicable diseases, namely, cancer and cardiovascular disorders. However, in some other settings the phenolic hydroxyl group of estrogens may be responsible for the anti-oxidative beneficial functions and thus protect against cardiovascular and neurodegenerative diseases. SCOPE OF REVIEW: To date, no single review article has mentioned the implication of estrogen receptors in both the pro-oxidative and anti-oxidative actions of estrogens. MAJOR CONCLUSION: The controversial role of estrogens as pro-oxidant or anti-oxidant is largely dependent on cell types, ratio of different types of estrogen receptors present in a particular cell and context specificity of the estrogen hormone responses. Both pro-oxidant and anti-oxidant effects of estrogens might involve different estrogen receptors that can have either genomic or non-genomic action to manifest further hormonal response. GENERAL SIGNIFICANCE: This review highlights the role of estrogen receptors in the pro-oxidative and anti-oxidative actions of estrogens with special emphasis on neuronal cells.

Implication of receptor for advanced glycation end product (RAGE) in pulmonary health and pathophysiology.

Receptor for advanced glycation end products (RAGE) is a membrane bound receptor and member of the immunoglobulin super family and is normally present in a highly abundant basal level expression in lung. This high expression of RAGE in lung alveolar epithelial type I (ATI) cells is presumably involved in the proliferation and differentiation of pulmonary epithelial cells. However, typically higher than basal level expression of RAGE may indicate the existence of severe pathophysiological condition in lung, e.g. acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). During pulmonary tissue injury an endogenous secretory isoform of RAGE called EsRAGE is noticed at high levels in broncho-alveolar lavage (BAL) and plasma. Recently, a soluble form of RAGE (sRAGE) produced by recombinant gene technology was shown to exhibit a therapeutic potential in experimental animal models. Detailed study of RAGE in the pulmonary tissues will facilitate the understanding of the importance of RAGE signaling in the pulmonary health and pathophysiology.

High concentration of antioxidants N-acetylcysteine and mitoquinone-Q induces intercellular adhesion molecule 1 and oxidative stress by increasing intracellular glutathione.

In endothelial cells, the intracellular level of glutathione is depleted during offering protection against proinflammatory cytokine TNF-alpha-induced oxidative stress. Administration of anti-inflammatory drugs, i.e., N-acetylcysteine (NAC) or mitoquinone-Q (mito-Q) in low concentrations in the human pulmonary aortic endothelial cells offered protection against depletion of reduced glutathione and oxidative stress mediated by TNF-alpha. However, this study addressed that administration of NAC or mito-Q in high concentrations resulted in a biphasic response by initiating an enhanced generation of both reduced glutathione and oxidized glutathione and enhanced production of reactive oxygen species, along with carbonylation and glutathionylation of the cellular proteins. This study further addressed that IkappaB kinase (IKK), a phosphorylation-dependent regulator of NF-kappaB, plays an important regulatory role in the TNF-alpha-mediated induction of the inflammatory cell surface molecule ICAM-1. Of the two catalytic subunits of IKK (IKKalpha and IKKbeta), low concentrations of NAC and mito-Q activated IKKalpha activity, thereby inhibiting the downstream NF-kappaB and ICAM-1 induction by TNF-alpha. High concentrations of NAC and mito-Q instead caused glutathionylation of IKKalpha, thereby inhibiting its activity that in turn enhanced the downstream NF-kappaB activation and ICAM-1 expression by TNF-alpha. Thus, establishing IKKalpha as an anti-inflammatory molecule in endothelial cells is another focus of this study. This is the first report that describes a stressful situation in the endothelial cells created by excess of antioxidative and anti-inflammatory agents NAC and mito-Q, resulting in the generation of reactive oxygen species, carbonylation and glutathionylation of cellular proteins, inhibition of IKKalpha activity, and up-regulation of ICAM-1expression.

Role of TNFalpha in pulmonary pathophysiology.

Tumor necrosis factor alpha (TNFalpha) is the most widely studied pleiotropic cytokine of the TNF superfamily. In pathophysiological conditions, generation of TNFalpha at high levels leads to the development of inflammatory responses that are hallmarks of many diseases. Of the various pulmonary diseases, TNFalpha is implicated in asthma, chronic bronchitis (CB), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In addition to its underlying role in the inflammatory events, there is increasing evidence for involvement of TNFalpha in the cytotoxicity. Thus, pharmacological agents that can either suppress the production of TNFalpha or block its biological actions may have potential therapeutic value against a wide variety of diseases. Despite some immunological side effects, anti-TNFalpha therapeutic strategies represent an important breakthrough in the treatment of inflammatory diseases and may have a role in pulmonary diseases characterized by inflammation and cell death.

Bridging advanced glycation end product, receptor for advanced glycation end product and nitric oxide with hormonal replacement/estrogen therapy in healthy versus diabetic postmenopausal women: a perspective.

Cardiovascular diseases (CVD) are the most significant cause of death in postmenopausal women. The loss of estrogen biosynthesis with advanced age is suggested as one of the major causes of higher CVD in postmenopausal women. While some studies show beneficial effects of estrogen therapy (ET)/hormonal replacement therapy (HRT) in the cardiovascular system of healthy postmenopausal women, similar studies in diabetic counterparts contradict these findings. In particular, ET/HRT in diabetic postmenopausal women results in a seemingly detrimental effect on the cardiovascular system. In this review, the comparative role of estrogens is discussed in the context of CVD in both healthy and diabetic postmenopausal women in regard to the synthesis or expression of proinflammatory molecules like advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGEs), inducible nitric oxide synthases (iNOS) and the anti-inflammatory endothelial nitric oxide synthases (eNOS). The interaction of AGE-RAGE signaling with molecular nitric oxide (NO) may determine the level of reactive oxygen species (ROS) and influence the overall redox status of the vascular microenvironment that may further determine the ultimate outcome of the effects of estrogens on the CVD in healthy versus diabetic women.

The role of reactive oxygen species in TNFalpha-dependent expression of the receptor for advanced glycation end products in human umbilical vein endothelial cells.

Engagement of the receptor for advanced glycation end products (RAGE) by its signal transduction ligands is implicated in the development and progression of atherosclerosis. TNFalpha, a proinflammatory cytokine, is a potent inducer of RAGE expression in endothelial cells. In the present study, we demonstrate that reactive oxygen species (ROS) generated by TNFalpha stimulated human umbilical vein endothelial cells (HUVECs) induce RAGE expression. The complex III of mitochondrial respiratory chain appears to be the primary source of ROS. The gp91phox subunit of NADPH oxidase appears to be the source of ROS that induces TNFalpha-dependent mitochondrial ROS generation and subsequent RAGE expression. We also demonstrate that the ROS-mediated RAGE induction occurs via activation of NF-kappaB, a proinflammatory transcription factor. Thus, stimulation of HUVECs by TNFalpha evokes the following sequence of events: stimulation of NADPH oxidase --> generation of ROS --> activation of the mitochondrial respiratory chain --> stimulation of NF-kappaB activity --> induction of RAGE expression.

Oxidized phospholipid-induced endothelial cell/monocyte interaction is mediated by a cAMP-dependent R-Ras/PI3-kinase pathway.

OBJECTIVE: Previous studies have demonstrated the importance of endothelial apical expression of connecting segment-1 (CS-1) fibronectin in mediating the entry of monocytes into atherosclerotic lesions and other sites of chronic inflammation. We previously demonstrated that oxidized PAPC (OxPAPC) increases monocyte-specific binding to arterial endothelium by causing deposition of CS-1 fibronectin on apical alpha5beta1 integrin. The present studies identify important signal transduction components regulating this pathway. METHODS AND RESULTS: Using endothelial cells in culture, we demonstrate that activation of R-Ras is responsible for CS-1-mediated monocyte binding. Although few natural activators of R-Ras have been demonstrated, OxPAPC activated endothelial R-Ras by 2.5-fold but decreased levels of activated H-Ras. The importance of R-Ras/H-Ras balance in regulating monocyte binding was shown by overexpression studies. Constitutively active R-Ras enhanced monocyte adhesion, whereas coexpression with constitutively active H-Ras was inhibitory. Elevated cAMP, mediated by OxPAPC and specific components POVPC and PEIPC, was responsible for R-Ras activation, and dibutyryl cAMP and pertussis toxin were also effective activators of R-Ras. Using inhibitor and dominant-negative constructs, we demonstrated that phosphatidylinositol 3-kinase (PI3K) was a key downstream effector of R-Ras in this pathway. CONCLUSIONS: OxPAPC, POVPC, and PEIPC induce a cAMP/R-Ras/PI3K signaling pathway that contributes to monocyte/endothelial cell adhesion and potentially atherosclerosis.