Receptor for Advanced Glycation End Products (RAGE) and Its Polymorphic Variants as Predictive Diagnostic and Prognostic Markers of NSCLCs: a Perspective.

PURPOSE OF REVIEW: Non-small cell lung cancers (NSCLCs) account for ~ 85% of all lung cancers, and 5-year survival in Europe and the USA is ~ 13-17%. In this review, we focus on the significance of Receptor for Advanced Glycation End products (RAGE) as a diagnostic or post-therapeutic prognostic marker for various forms of NSCLCs. RECENT FINDINGS: The lungs have the highest levels of basal RAGE expression in mammals. The physiologic RAGE in lungs may be involved in adhesion and spreading of AT-1 cells and maintenance of pulmonary homeostasis. However, high level expression of RAGE complicates various diseases including acute lung injury. In NSCLCs, while a number of studies report decreased RAGE expression, inferring a protective role, others suggest that RAGE expression may contribute to NSCLC pathogenesis. Genetic polymorphisms of RAGE are reportedly associated with NSCLC development and complications. RAGE and its polymorphic variants may be useful diagnostic or post-therapeutic prognostic markers of NSCLCs.

Role of receptor for advanced glycation end products in the complication and progression of various types of cancers.

BACKGROUND: Receptor for advanced glycation end-products popularly known as RAGE is a cell surface immunoglobulin class of molecule, binds with multiple ligands and therefore considered as a multi-ligand receptor. Use of RAGE deficient mice (RAGE(-/-)) as well as established mouse models pertaining to inflammation-associated carcinogenesis such as that of chemically induced carcinogenesis and colitis associated cancer provides a direct genetic evidence for a likelihood novel role of RAGE in cancer, with respect to its ability to lead cancer cell proliferation and survival. Besides inflammation, interaction of RAGE with its various ligands enhances oxidative stress both in cancerous and noncancerous cells which further complicates the progression of cancers. SCOPE OF REVIEW: Till date, no single review article has discussed the mechanism of RAGE dependent complication of cancers, particularly the role of RAGE in cancer cell proliferation, angiogenesis, survival and anti-apoptosis needs to be discussed. MAJOR CONCLUSION: RAGE enhances the number of cancer cells by activating the cell cycle proteins (e.g., cyclin D1), anti-apoptotic proteins (e.g., BCl2), prosurvival (AKT) and autophagic proteins. Role of RAGE has also been detected in formation of new blood vessels (angiogenesis) in the cancer cells and activation of myeloid derived suppressor cells (MDSCs). GENERAL SIGNIFICANCE: This review article describes the role of RAGE in the complication of various types of cancers and the possible usefulness of RAGE dependent therapy to confront cancers in a stronger magnitude.

Arsenic and 17-ß-estradiol bind to each other and neutralize each other's signaling effects.

We report that arsenic trioxide (ATO) and 17-beta-estradiol (E2) abolish each other's independent cell signaling effects in respect of cell survival and proliferation/migration of breast cancer (MCF-7) cells. The possibility that this is due to binding of ATO to E2 was confirmed through difference absorption spectroscopy, chromatography-coupled voltammometry and 1-D (1)H and (13)C NMR spectroscopy. Binding leads to attenuation of E2's hydroxyl (1)H peaks at its C17 and C3 carbon positions. The results suggest that ATO and E2 can titrate each other's levels, potentially explaining why sustained arsenic exposure tends to be associated with delays in age of menarche, advanced age of menopause, poorer sperm quality, higher overall morbidity in men, and lower incidences of breast cancer in women in some arsenic-contaminated areas.

Knockdown of receptor for advanced glycation end products attenuate 17α-ethinyl-estradiol dependent proliferation and survival of MCF-7 breast cancer cells.

BACKGROUND: 17α-ethinyl-estradiol (17α-EE), a synthetic estrogen is the world's most widely and commonly used orally bioactive estrogen. Currently, 17α-EE is in use in all formulations of contraceptive pills and is implicated in the complication of breast cancer. Receptor for advanced glycation end products (RAGE) is a cell surface immunoglobulin class of molecule. RAGE is involved in the complication of various cancers. METHODS AND RESULTS: This study indicates that treatment of MCF-7 breast cancer cells with 17α-EE enhances the expression of estrogen receptor related receptor gamma (ERRγ), followed by enhanced level of oxidative stress and subsequent activation of the transcription factor, nuclear factor kappa-B (NF-кB), leading to increase in RAGE expression. RAGE thus expressed by 17α-EE treatment causes further enhancement of the oxidative stress which, in turn, activates expression of cell cycle protein cyclin D1 and subsequent induction of MCF-7 breast cancer cell proliferation. RAGE also enhanced phosphorylation of prosurvival protein AKT and increased expression of Bcl2, an antiapoptotic protein. CONCLUSION: In MCF-7 breast cancer cells, 17α-EE-ERRγ interaction induces the expression of RAGE, which in turn, enhances the number of MCF-7 breast cancer cells through a multiprong action on the divergent molecules like cyclin D1, AKT and Bcl2. GENERAL SIGNIFICANCE: This is the first report which explains the intermediate role of ERRγ in the 17α-EE dependent RAGE expression in MCF-7 breast cancer cells. This report for the first time explains that RAGE is important not only for MCF-7 breast cancer cell proliferation but also for its survival and anti-apoptotic activities.

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.

Advances in nanotechnology for diagnosis and treatment of tuberculosis.

PURPOSE OF REVIEW: Tuberculosis (TB) has been a most turbulent problem prevailing for the last several decades. The emergence of multidrug-resistant strains and the dearth of anti-TB drugs are threatening the future containment of TB. Nanotechnology presents an exciting opportunity for proper identification of mycobacterial strains and to improve the potential of drugs for the treatment of TB. RECENT FINDINGS: Nanoscience has provided humankind with several unique and comparatively more effective drug delivery carriers, encompassing liposomal-mediated drug delivery, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, nanoemulsions, nanosuspensions and other nanosystems exploiting the extraordinary properties of matter at the nanoscale. Nanoparticle-based assays have shown significant improvements in diagnosis, treatment and prevention of TB. Nanoparticles as drug carriers enable higher stability and carrier capacity along with immense improvement of drug bioavailability which further leads to reduction in dosage frequency. SUMMARY: This review covers the prospect of using nanotechnology for the detection of mycobacterial strains and nanotechnology-based drug delivery systems for effective eradication of mycobacterial infections.

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.

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.

The emerging role of estrogen related receptorα in complications of non-small cell lung cancers.

Approximately 85% of lung cancer cases are recognized as non-small cell lung cancer (NSCLC) with a perilous (13-17%) 5-year survival in Europe and the USA. Although tobacco smoking has consistently emerged as the leading cause of NSCLC complications, its consequences are distinctly manifest with respect to sex bias, due to differential gene and sex hormone expression. Estrogen related receptor α (ERRα), a member of the nuclear orphan receptor superfamily is normally expressed in the lungs, and activates various nuclear genes without binding to the ligands, such as estrogens. In NSCLC ERRα expression is significantly higher compared with healthy individuals. It is well established ERα and ERß' have 93% and 60% identity in the DNA and ligand binding domains, respectively. ERα and ERRα have 69% (70% with ERRα-1) and 34% (35% with ERRα-1) identity, respectively; ERRα and ERRß' have 92 and 61% identity, respectively. However, whether there is distinctive ERRα interaction with mammalian estrogens or concurrent involvement in non-ER signalling pathway activation is not known. Relevant to NSCLC, ERRα promotes proliferation, invasion and migration by silencing the tumor suppressor proteins p53 and pRB, and accelerates G2-M transition during cell division. Epithelial to mesenchymal transition (EMT) and activation of Slug (an EMT associated transcription factor) are the prominent mechanisms by which ERRα activates NSCLC metastasis. Based on these observations, the present article focuses on the feasibility of antiERRα therapy alone and in combination with antiER as a therapeutic strategy for NSCLC complications.

Recent Advances in Curcumin Treated Non-Small Cell Lung Cancers: An Impetus of Pleiotropic Traits and Nanocarrier Aided Delive ry.

Characterized by the abysmal 18% five year survival chances, non-small cell lung cancers (NSCLCs) claim more than half of their sufferers within the first year of being diagnosed. Advances in biomedical engineering and molecular characterization have reduced the NSCLC diagnosis via timid screening of altered gene expressions and impaired cellular responses. While targeted chemotherapy remains a major option for NSCLCs complications, delayed diagnosis, and concurrent multi-drug resistance remain potent hurdles in regaining normalcy, ultimately resulting in relapse. Curcumin administration presents a benign resolve herein, via simultaneous interception of distinctly expressed pathological markers through its pleiotropic attributes and enhanced tumor cell internalization of chemotherapeutic drugs. Studies on NSCLC cell lines and related xenograft models have revealed a consistent decline in tumor progression owing to enhanced chemotherapeutics cellular internalization via co-delivery with curcumin. This presents an optimum readiness for screening the corresponding effectiveness in clinical subjects. Curcumin is delivered to NSCLC cells either (i) alone, (ii) in stoichiometrically optimal combination with chemotherapeutic drugs, (iii) through nanocarriers, and (iv) nanocarrier co-delivered curcumin and chemotherapeutic drugs. Nanocarriers protect the encapsulated drug from accidental and non-specific spillage. A unanimous trait of all nanocarriers is their moderate drug-interactions, whereby native structural expressions are not tampered. With such insights, this article focuses on the implicit NSCLC curative mechanisms viz-a-viz, free curcumin, nanocarrier delivered curcumin, curcumin + chemotherapeutic drug and nanocarrier assisted curcumin + chemotherapeutic drug delivery.

Metastable bound (1,3)D(o) states below N=3 ionization threshold of He+.

The applicability of Ritz-variational principle for 3dnf ((1,3)D(o)) states lying between N=2 and N=3 ionization threshold of singly ionized helium is discussed in this communication. Probable existence of such a state for O(6+) within the planetary atmosphere in the polar regions of Jupiter is discussed.

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.

Recent advances in gold and silver nanoparticle based therapies for lung and breast cancers.

In recent years, gold (Au) and silver (Ag) nanoparticles (NPs) have been the centerstage of improving cancer treatments and therapies, substantially attributed to their size and shape tuneable chemical, optical and photonic properties. Owing to such specialties, diverse shapes of Au and Ag NPs have enabled an efficient cellular uptake along with remarkable improvements in early stage diagnosis of tumors. Robust synthesis methods employing several reducing agents have been the backbone of such enormous strides of Au and Ag NPs, allowing the delivery of much lower drug volumes to minimize the patient sensitization. Probes based on Au and Ag NPs functionalization with biocompatible chemical molecules have substantially improved their in vivo tracking and mediating a site-specific binding leading to improved cancer treatment with minimal risks to normal cells. With a better drug delivery potential of non-spherical shapes, the cylindrical (rod shaped) geometries have recently been investigated to possess higher cellular uptake. The rod shaped surface morphology enables a larger area for drug binding with enhanced possibility to make use of photothermal attributes. The interplay of size and shape dependent biologic activities is regulated by physicochemical changes in the tumor microenvironment, where stable drug-carrier binding is facilitated by surface modification of NPs, through moderate interactive forces ensuring minimal changes in native drug structure. The energy savvy greener methods, like microwave and microemulsions have enabled much better control on the synthesized nanoparticle shapes and geometries, through a regulation of precursor to reducing agent stoichiometries. With this viewpoint, this article focuses on most common synthesis methods of Au and Ag NPs alongside their application in more effective treatment of lung and breast cancers.

Kaempferol - A dietary anticancer molecule with multiple mechanisms of action: Recent trends and advancements.

The consumption of diet-based naturally bioactive metabolites is preferred to synthetic material in order to avert health-associated disorders. Among the plant-derived polyphenols, kaempferol (KMF) is considered as a valuable functional food ingredient with a broad range of therapeutic applications such as anti-cancer, antioxidant and anti-inflammatory uses. KMF acts on a range of intracellular as well as extracellular targets involved in the cell signaling pathways that in turn are known to regulate the hallmarks of cancer growth progressions like apoptosis, cell cycle, invasion or metastasis, angiogenesis and inflammation. Importantly, the understanding of mechanisms of action of KMF-mediated therapeutic effects may help the scientific community to design novel strategies for the treatment of dreadful diseases. The current review summarizes the various types of molecular targets of KMF in cancer cells as well as other health-associated disorders. In addition, this review also highlights the absorption, metabolism and epidemiological findings.

Mechanistic insight into carnosol-mediated pharmacological effects: Recent trends and advancements.

For several decades, bioactive phytochemicals have been appreciated to prevent and cure various lethal diseases. Many studies have proven the ability of dietary phytochemicals to avoid and retard tumor initiation and progression. Among the pharmacologically active moieties, terpenoids are considered one of the most important classes. Carnosol, is also a kind of diterpenoid, which known to possess a range of therapeutic effects such as anti-cancer, anti-inflammatory, and anti-oxidant activities. All these effects are mediated via modulating different signaling cascades, including apoptosis regulating molecules (Bax/Bcl2), prosurvival-proproliferative molecules (Akt/mTOR, MAPK), transcription factors like NF-kappaB, STAT3-6, and steroid receptors, such as androgen and estrogen receptors. The present review highlights the recent trends and advancements have been done in the field of research by using carnosol.

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.

Differential effect of estrogen receptor alpha and beta agonists on the receptor for advanced glycation end product expression in human microvascular endothelial cells.

Estrogens are known to induce the expression of the receptor for advanced glycation end products (RAGE). In the current investigation, we examined the effect of three estrogens with different potency for specific estrogen receptors (ER) on RAGE expression in human microvascular endothelial cells (HMEC-1). Of the three estrogens tested, ethinyl estradiol (EE), an estrogen receptor alpha (ERalpha) agonist, was the strongest inducer of RAGE expression in HMEC-1. By comparison, 17-epiestriol, an estrogen receptor beta (ERbeta) agonist and 17-beta-E2, an ER agonist that is almost equally potent for ERalpha and ERbeta were less effective in stimulating RAGE expression. We then determined whether the prooxidative and proinflammatory transcription factors Sp1 or NF-kappaB were downstream modulators of ER-agonists that mediate RAGE expression. The results implicated Sp1 but not NF-kappaB in estrogen-dependent RAGE expression. We further demonstrated that ERalpha but not ERbeta was responsible for the estrogen-mediated Sp1 activation. In summary, the present investigation demonstrates that a direct interaction of EE-ERalpha-Sp1 plays a central role in estrogen-induced RAGE expression in HMEC-1.

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.

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.

Role of Reactive Oxygen Species in Estrogen Dependant Breast Cancer Complication.

ROS have vital roles in cellular signaling and homeostasis. At low concentration, ROS promotes cancer cell survival by the activation of growth factors and MAP-kinases (MAPKs) that further activates cell cycle progression. At high concentration, ROS produces oxidative stress that activates programmed cell death or apoptosis. However, this fine distinction of ROS action either as a growth promoter or pro-apoptotic agent depends not only on dosage (concentration) but also on the duration, type, and site of ROS generation. The female steroid estrogens and their various metabolites generate ROS in the breast cancer cells. Slow, sustained and moderate level of ROS generated by estrogens and their metabolites cause initiation and progression of breast cancer. ROS generated by estrogens affect pro-proliferative (e.g. cyclin D1, Cdc2), prosurvival (e.g. AKT), antiapoptotic (e.g. BCl2) and pro-inflammatory (e.g. NF-κB) molecules. These multipronged actions of ROS lead to the activation of several signaling pathways involved in the breast cancer cell survival and proliferation, resulting in the progression of breast cancer. Present review article provides insights into the role of estrogen generated ROS and its associated signaling pathways in the initiation and progression of breast cancer. The importance of ROS as breast cancer drug target has also been discussed.