Extensive development of inhaled and oral glucocorticoids has resulted in highly potent molecules that have been optimized to target activity to the lung and minimize systemic exposure. These have proved highly effective for most asthmatic subjects, but despite these developments, there are a number of subjects with asthma who fail to respond to even high doses of inhaled or even oral glucocorticoids. Advances in delineating the fundamental mechanisms of glucocorticoid pharmacology, especially the concepts of transactivation and transrepression and cofactor recruitment, have resulted in better understanding of the molecular mechanisms whereby glucocorticoids suppress inflammation. The existence of multiple mechanisms underlying glucocorticoid insensitivity raises the possibility that this might indeed reflect different diseases with a common phenotype, and studies examining the efficacy of potential new agents should be targeted toward subgroups of patients with severe corticosteroid-resistant asthma who clearly require effective new drugs and other approaches to improved asthma control.

Update on glucocorticoid action and resistance

The direct targets of extremely low and microwave frequency range electromagnetic fields (EMFs) in producing non-thermal effects have not been clearly established. However, studies in the literature, reviewed here, provide substantial support for such direct targets. Twenty-three studies have shown that voltage-gated calcium channels (VGCCs) produce these and other EMF effects, such that the L-type or other VGCC blockers block or greatly lower diverse EMF effects. Furthermore, the voltage-gated properties of these channels may provide biophysically plausible mechanisms for EMF biological effects. Downstream responses of such EMF exposures may be mediated through Ca2+ /calmodulin stimulation of nitric oxide synthesis. Potentially, physiological/therapeutic responses may be largely as a result of nitric oxide-cGMP-protein kinase G pathway stimulation. A well-studied example of such an apparent therapeutic response, EMF stimulation of bone growth, appears to work along this pathway. However, pathophysiological responses to EMFs may be as a result of nitric oxide-peroxynitrite-oxidative stress pathway of action. A single such well-documented example, EMF induction of DNA single-strand breaks in cells, as measured by alkaline comet assays, is reviewed here. Such single-strand breaks are known to be produced through the action of this pathway. Data on the mechanism of EMF induction of such breaks are limited; what data are available support this proposed mechanism. Other Ca2+ -mediated regulatory changes, independent of nitric oxide, may also have roles. This article reviews, then, a substantially supported set of targets, VGCCs, whose stimulation produces non-thermal EMF responses by humans/higher animals with downstream effects involving Ca2+ /calmodulin-dependent nitric oxide

/pdf/electromagnetic-fields-act-via-activation-of-voltage-gated-3zr1b13ez6.pdf

Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects

proceedings, in not being up-to-date. There are almost no references to papers later than 1990, except for some self-citations which extend to 1991. In addition to well known major contributors to the field of metastasis, research participants were also drawn from laboratories in Continental Europe, which are not frequently represented at Symposia of this type. Some of the papers are general overviews, while others report the Authors own studies in detail. On the whole the various contributions are rather disparate, but occasionally authors compare and contrast a related phenomenon. An example is the role of the CD-44, a transmembrane protein involved in lymphocyte transport, for which the group of Herrlich (Karlsruhe, Germany) have obtained convincing evidence of a role in metastasis. On the other hand, I.R. Hart (London, UK) described studies involving a panel of melanoma cells in which no evidence for a direct involvement of CD-44 in metastasis was found. The subject matter is divided into the following sections: The first section has papers dealing with the role of ras oncogenes and bladder carcinoma and the initial steps in cancer dissemination of rat bladder carcinoma. These raise questions without providing any answers. The second section is concerned principally with cell adhesion and highlights complexity and conflicting results. In the third section the discussion of angiogenesis is disappointing and work is reported from investigators who are not prominent in the area. There is, however, a very valuable chapter from L. Weiss (Buffalo, New York). He analyses, in detail, a mechanism for the destruction of cancer cells in the microvasculature based on deformation. Weiss' data for the destruction of cancer cells when trapped in capillaries has long been a key observation in the field of blood-borne metastatic spread. It leads to the concept of metastatic inefficiency which is so evident when the relative infrequency of metastasis is compared with the number of cancer cells shed into the circulation. Weiss' suggestion as to how this destruction occurs is compelling and he provides most interesting new data which indicates that treatment of cells with doxorubicin increases biomechanical destruction. In the section on melanoma there are two rather unconvincing contributions on metastasis-associated surface molecules, in addition to the critical analysis of the role of CD-44 to which reference has already been made. The last two sections contain a mixture of topics and on the whole are of little interest. Immunotherapy with autologous tumour 'vaccines' …

Protein Kinase C

Glucocorticoids (GCs) are steroidal ligands for the GC receptor (GR), which can function as a ligand-activated transcription factor. These steroidal ligands and derivatives thereof are the first line of treatment in a vast array of inflammatory diseases. However, due to the general surge of side effects associated with long-term use of GCs and the potential problem of GC resistance in some patients, the scientific world continues to search for a better understanding of the GC-mediated antiinflammatory mechanisms. The reversible phosphomodification of various mediators in the inflammatory process plays a key role in modulating and fine-tuning the sensitivity, longevity, and intensity of the inflammatory response. As such, the antiinflammatory GCs can modulate the activity and/or expression of various kinases and phosphatases, thus affecting the signaling efficacy toward the propagation of proinflammatory gene expression and proinflammatory gene mRNA stability. Conversely, phosphorylation of GR can affect GR ligand- and DNA-binding affinity, mobility, and cofactor recruitment, culminating in altered transactivation and transrepression capabilities of GR, and consequently leading to a modified antiinflammatory potential. Recently, new roles for kinases and phosphatases have been described in GR-based antiinflammatory mechanisms. Moreover, kinase inhibitors have become increasingly important as antiinflammatory tools, not only for research but also for therapeutic purposes. In light of these developments, we aim to illuminate the integrated interplay between GR signaling and its correlating kinases and phosphatases in the context of the clinically important combat of inflammation, giving attention to implications on GC-mediated side effects and therapy resistance.

Crosstalk in inflammation :The interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases

Evolution of the corticosteroid receptor signalling pathway in fish.

The present study investigates the effect of free radical formation due to mobile phone exposure and effect on fertility pattern in 70-day-old male Wistar rats (sham exposed and exposed). Exposure took place in Plexiglas cages for 2 h a day for 35 days to mobile phone frequency. The specific absorption rate was estimated to be 0.9 W/kg. An analysis of antioxidant enzymes glutathione peroxidase (P < 0.001) and superoxide dismutase (P < 0.007) showed a decrease, while an increase in catalase (P < 0.005) was observed. Malondialdehyde (P < 0.003) showed an increase and histone kinase (P = 0.006) showed a significant decrease in the exposed group. Micronuclei also show a significant decrease (P < 0.002) in the exposed group. A significant change in sperm cell cycle of G0–G1 (P = 0.042) and G2/M (P = 0.022) were recorded. Generation of free radicals was recorded to be significantly increased (P = 0.035). Our findings on antioxidant, malondialdehyde, histone kinase, micronuclei, and sperm cell cycle are clear indications of an infertility pattern, initiated due to an overproduction of reactive oxygen species. It is concluded that radiofrequency electromagnetic wave from commercially available cell phones might affect the fertilizing potential of spermatozoa.

Effects of radiofrequency electromagnetic wave exposure from cellular phones on the reproductive pattern in male Wistar rats.

Intracellular localization and nucleocytoplasmic trafficking of steroid receptors: an overview.

Recently, there have been several reports referring to detrimental effects due to radio frequency electromagnetic fields (RF-EMF) exposure. Special attention was given to investigate the effect of mobile phone exposure on the rat brain. Since the integrative mechanism of the entire body lies in the brain, it is suggestive to analyze its biochemical aspects. For this, 35-day old Wistar rats were exposed to a mobile phone for 2 h per day for a duration of 45 days where specific absorption rate (SAR) was 0.9 W/Kg. Animals were divided in two groups: sham exposed (n = 6) and exposed group (n = 6).Our observations indicate a significant decrease (P < 0.05) in the level of glutathione peroxidase, superoxide dismutase, and an increase in catalase activity. Moreover, protein kinase shows a significant decrease in exposed group (P < 0.05) of hippocampus and whole brain. Also, a significant decrease (P < 0.05) in the level of pineal melatonin and a significant increase (P < 0.05) in creatine kinase and caspase 3 wa...

900-MHz microwave radiation promotes oxidation in rat brain.

A significant decrease in protein kinase C and total sperm count along with increased apoptosis were observed in male Wistar rats exposed to mobile phone frequencies (2 h/day x 35 days at 0.9 W/kg specific absorption rate). The results suggest that a reduction in protein kinase activity may be related to overproduction of reactive oxygen species (ROS) under microwave field exposure. Decrease in sperm count and an increase in apoptosis may be causative factor due to mobile radiation exposure leading to infertility.

http://nopr.niscair.res.in/bitstream/123456789/10343/1/IJEB%2048(10)%20987-992.pdf

Mobile phone usage and male infertility in Wistar rats.

Purpose: To investigate the effect of 245 GHz microwave radiation on rat brain of male wistar strainMaterial and methods: Male rats of wistar strain (35 days old with 130 ± 10 g body weight) were selected for this study Animals were divided into two groups: Sham exposed and experimental Animals were exposed for 2 h a day for 35 days to 245 GHz frequency at 034 mW/cm2 power density The whole body specific absorption rate (SAR) was estimated to be 011 W/Kg Exposure took place in a ventilated Plexiglas cage and kept in anechoic chamber in a far field configuration from the horn antenna After the completion of exposure period, rats were sacrificed and the whole brain tissue was dissected and used for study of double strand DNA (Deoxyribonucleic acid) breaks by micro gel electrophoresis and the statistical analysis was carried out using comet assay (IV-2 version software) Thereafter, antioxidant enzymes and histone kinase estimation was also performedResults: A significant increase was observed in 

Sanjay Kumar

Papers

Effects of radiofrequency electromagnetic wave exposure from cellular phones on the reproductive pattern in male Wistar rats.

Intracellular localization and nucleocytoplasmic trafficking of steroid receptors: an overview.

900-MHz microwave radiation promotes oxidation in rat brain.

Mobile phone usage and male infertility in Wistar rats.

Mutagenic response of 2.45 GHz radiation exposure on rat brain