Simultaneous exposure to chronic irradiation and simulated microgravity differentially alters immune cell phenotype in mouse thymus and spleen.

Deep-space missions may alter immune cell phenotype in the primary (e.g., thymus) and secondary (e.g., spleen) lymphoid organs contributing to the progression of a variety of diseases. In deep space missions, astronauts will be exposed to chronic low doses of HZE radiation while being in microgravity. Ground-based models of long-term uninterrupted exposures to HZE radiation are not yet available. To obtain insight in the effects of concurrent exposure to microgravity and chronic irradiation (CIR), mice received a cumulative dose of chronic 0.5 Gy gamma rays over one month ± simulated microgravity (SMG). To obtain insight in a dose rate effect, additional mice were exposed to single acute irradiation (AIR) at 0.5 Gy gamma rays. We measured proportions of immune cells relative to total number of live cells in the thymus and spleen, stress level markers in plasma, and change in body weight, food consumption, and water intake. CIR affected thymic CD3+/CD335+ natural killer T (NK-T) cells, CD25+ regulatory T (Treg) cells, CD27+/CD335- natural killer (NK1) cells and CD11c+/CD11b- dendritic cells (DCs) differently in mice subjected to SMG than in mice with normal loading. No such effects of CIR on SMG as compared to normal loading were observed in cell types from the spleen. Differences between CIR and AIR groups (both under normal loading) were found in thymic Treg and DCs. Food consumption, water intake, and body weight were less after coexposure than singular or no exposure. Compared to sham, all treatment groups exhibited elevated plasma levels of the stress marker catecholamines. These data suggest that microgravity and chronic irradiation may interact with each other to alter immune cell phenotypes in an organ-specific manner and appropriate strategies are required to reduce the health risk of crewmembers.

The use of electronic nicotine delivery systems during pregnancy and the reproductive outcomes: A systematic review of the literature.

INTRODUCTION: Use of electronic nicotine delivery systems (ENDS) among pregnant women is of great concern. To our knowledge the current literature provides conflicting views regarding the uncertainties of the effects of ENDS use during pregnancy on the health of the fetus. METHODS: We searched PubMed, CINAHL, and EMBASE, for the period 2007 to October 2017 for terms to identify publications on ENDS use during pregnancy and the reproductive outcomes. We updated the search for the period November 2017 to November 2018 using Ovid Medline. We obtained full text of articles and present a summary of the contents. RESULTS: We found no studies of pregnant women exposed to ENDS use and its effect on their fetus or neonates. However, there is a growing body of experimental studies in animals that suggest that nicotine in ENDS alters DNA methylation, induces birth defects, reduces the birth weight, and affects the development of the heart and lungs of their offspring. A large population-based cohort study in the United States estimated that 5% of pregnant women were current ENDS users in 2014; most of them also smoked cigarettes. Surveys conducted among practitioners indicate that there is a need to screen and counsel pregnant women. Systematic reviews and meta-analysis of studies of women who used smokeless tobacco during pregnancy suggest that prenatal nicotine alone is a risk factor for low birth weight, premature delivery, and stillbirth. CONCLUSIONS: There were no previous studies assessing the reproductive effects of ENDS use during pregnancy. However, prenatal exposure to nicotine is known to be harmful to the fetus and the pregnancy.

Effects of a natural polyphenol on nicotine-induced pancreatic cancer cell proliferation.

INTRODUCTION: Resveratrol (trans-3, 4', 5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits, has anti-inflammatory and anti-oxidant effects. Its anti-carcinogenic effects are closely associated with its antioxidant activity; thus, the use of resveratrol as a possible cancer chemo-preventive is considered to be an important area of investigation. In this study we have examined the inhibitory effects of resveratrol in nicotine induced proliferation of pancreatic cancer cells. METHODS: Cultured AR42J cells were incubated with 100 µM nicotine for 3 min and with 100 µM resveratrol for 30 min, either alone or in combination. Proliferation assays were conducted for a period of 0 to 96 h in serum media, incubated with nicotine and resveratrol, and evaluated by MTT assay. Protein was measured in lysed cells and activation of MAPK signals was measured by western blot using purified p-ERK antibody. Co-localization of activated ERK signals was confirmed by FITC conjugated ERK antibody using immunofluorescence assay and confocal microscopy. Biomarker of lipid peroxidation was determined in cell lysates by malondialdehyde (MDA) bioassay. RESULTS: Resveratrol significantly suppressed the nicotine-induced proliferation of acinar cells compared to untreated controls (p<0.05). Mitogen activated protein kinase (MAPK) analysis revealed up-regulation of p-ERK expression by nicotine (p<0.05) that was suppressed significantly by resveratrol (p<0.05). Co-localization of activated ERK signals was confirmed by FITC conjugated ERK antibody, and this response was reduced significantly by resveratrol. Nicotine-induced malondialdehyde formation was also suppressed by resveratrol (p<0.05). CONCLUSIONS: The data suggest that resveratrol suppressed nicotine-induced AR42J cell proliferation. The proliferation of AR42J cells by nicotine is associated with activation of MAPK signals and induction of protein oxidation. Resveratrol suppressed lipid peroxidation and P-ERK activated signals induced by nicotine. We conclude that resveratrol acts as an effective antioxidant in reversing the nicotine induced pancreatic cancer cell proliferation.

Aminoguanidine (AG) Induces Induced both Pro- and Antioxidant Effect in AR42J Cells, a Rat Pancreatic Tumor Cell Line.

Aminoguanidine (AG), a diamine oxidase and a nitric oxide synthase inhibitor, was used in diabetes, thyroid follicular carcinoma, hepatocellular carcinoma, pancreatic cancer xenografts and in breast cancer research. The effects of AG on these pathologic conditions may be related to its regulatory effects on cell proliferation, angiogenesis, and expression of antioxidant enzymes. However, its role as pro and/or anti-oxidant affecting signaling and function in pancreatic tumor cell lines has not been studied. The current study tested the hypothesis that exposure of AR42J cells to aminoguanidine will induce pro-oxidant effects that may lead to increased proliferation and growth of these cells. METHODS: AR42J cells were grown in F-12 nutrient medium in 5% CO2 at 37°C to attain over 90% confluency before being treated with 20 uM hydrogen peroxide (H2O2) for 20 min and 100 uM AG for 30 min separately and in combination. Cell lysates collected from these experiments were measured for formation of lipid peroxides by malondialdehyde (MDA) assay and for activation of phospho-ERK 1/2 signal transduction by Western blotting. The activation of ERK signaling was further confirmed by immunohistochemical analysis. Effect of ERK1/2 on cell proliferation in response to AG and H2O2 was evaluated by MTT assay while the functional status of AR42J cells was determined by release of amylase following CCK-8 stimulation. RESULTS: MDA concentration in cells treated with AG was not different from untreated cells. However, treatment with H2O2 either alone or in combination with AG increased MDA significantly (p<0.05). AG treatment alone induced 3.5 fold activation of pERK-1/2, as compared to 2.5 fold increase with H2O2 alone (p<0.05) as compared to untreated control. The results of ERK activation were confirmed further by its co-localization employing FITC-conjugated ERK antibody. AG -induced maximal cell proliferation occurred at 48 hr. incubation (p<0.05); these values were not significantly different from that of H2O2 treated and control cells. Cell function (CCK-stimulated amylase release) was significantly enhanced by AG (p<0.05). CONCLUSION: These data suggest that in an in-vitro system, AG acts as a pro-oxidant on AR42J cell proliferation and possibly affects the resulting function.

Degenerative Tissue Responses to Space-like Radiation Doses in a Rodent Model of Simulated Microgravity.

This study examines acute and degenerative tissue responses to space-like radiation doses in a rodent model of simulated microgravity. We have studied four groups of rats, control (CON), irradiated (IR), irradiated and hindlimb suspended (IR-HLS), and suspended (HLS) that were maintained for two weeks. IR and IR+HLS groups were exposed to five sessions of X-ray irradiation (1.2 Gy each, at 3-4 days intervals). Body weights, soleus muscle weights, and hindlimb bone mineral density (BMD) were measured. Results show that compared to CON animals, IR, HLS, and IR+HLS group reduced the body weight gain significantly. IR-associated growth retardation appeared to be closely linked to acute and transient post-IR 'anorexia' (a decrease in food intake). HLS but not IR induced major changes in the musculoskeletal system, consisting in decreases in soleus muscle mass and bone mineral density of distal femur and proximal tibia. Additional dosimetric studies showed that the effect of IR on weight is detectable at 0.3 Gy X-ray doses, while no threshold dose for the IR-produced decrease in food intake could be observed. This study suggests that space flight-associated anorexia and musculoskeletal degenerative changes may be driven by different, radiation- and microgravity-associated (respectively) mechanisms.

Animal model of simulated microgravity: a comparative study of hindlimb unloading via tail versus pelvic suspension.

The aim of this study was to compare physiological effects of hindlimb suspension (HLS) in tail- and pelvic-HLS rat models to determine if severe stretch in the tail-HLS rats lumbosacral skeleton may contribute to the changes traditionally attributed to simulated microgravity and musculoskeletal disuse in the tail-HLS model. Adult male Sprague-Dawley rats divided into suspended and control-nonsuspended groups were subjected to two separate methods of suspension and maintained with regular food and water for 2 weeks. Body weights, food and water consumption, soleus muscle weight, tibial bone mineral density, random plasma insulin, and hindlimb pain on pressure threshold (PPT) were measured. X-ray analysis demonstrated severe lordosis in tail- but not pelvic-HLS animals. However, growth retardation, food consumption, and soleus muscle weight and tibial bone density (decreased relative to control) did not differ between two HLS models. Furthermore, HLS rats developed similar levels of insulinopenia and mechanical hyperalgesia (decreased PPT) in both tail- and pelvic-HLS groups. In the rat-to-rat comparisons, the growth retardation and the decreased PPT observed in HLS-rats was most associated with insulinopenia. In conclusion, these data suggest that HLS results in mild prediabetic state with some signs of pressure hyperalgesia, but lumbosacral skeleton stretch plays little role, if any, in these pathological changes.

Effect of nicotine on exocytotic pancreatic secretory response: role of calcium signaling.

BACKGROUND: Nicotine is a risk factor for pancreatitis resulting in loss of pancreatic enzyme secretion. The aim of this study was to evaluate the mechanisms of nicotine-induced secretory response measured in primary pancreatic acinar cells isolated from Male Sprague Dawley rats. The study examines the role of calcium signaling in the mechanism of the enhanced secretory response observed with nicotine exposure. METHODS: Isolated and purified pancreatic acinar cells were subjected to a nicotine exposure at a dose of 100 µM for 6 minutes and then stimulated with cholecystokinin (CCK) for 30 min. The cell's secretory response was measured by the percent of amylase released from the cells in the incubation medium Calcium receptor antagonists, inositol trisphosphate (IP3) receptor blockers, mitogen activated protein kinase inhibitors and specific nicotinic receptor antagonists were used to confirm the involvement of calcium in this process. RESULTS: Nicotine exposure induced enhanced secretory response in primary cells. These responses remained unaffected by mitogen activated protein kinases (MAPK's) inhibitors. The effects, however, have been completely abolished by nicotinic receptor antagonist, calcium channel receptor antagonists and inositol trisphosphate (IP3) receptor blockers. CONCLUSIONS: The data suggest that calcium activated events regulating the exocytotic secretion are affected by nicotine as shown by enhanced functional response which is inhibited by specific antagonists… The results implicate the role of nicotine in the mobilization of both intra- and extracellular calcium in the regulation of stimulus-secretory response of enzyme secretion in this cell system. We conclude that nicotine plays an important role in promoting enhanced calcium levels inside the acinar cell.

Molecular signaling mechanisms of apoptosis in hereditary non-polyposis colorectal cancer.

Colorectal cancer is the second most leading cause of cancer related deaths in the western countries. One of the forms of colorectal cancer is hereditary non-polyposis colorectal cancer (HNPCC), also known as "Lynch syndrome". It is the most common hereditary form of cancer accounting for 5%-10% of all colon cancers. HNPCC is a dominant autosomal genetic disorder caused by germ line mutations in mismatch repair genes. Human mismatch repair genes play a crucial role in genetic stability of DNA, the inactivation of which results in an increased rate of mutation and often a loss of mismatch repair function. Recent studies have shown that certain mismatch repair genes are involved in the regulation of key cellular processes including apoptosis. Thus, differential expression of mismatch repair genes particularly the contributions of MLH1 and MSH2 play important roles in therapeutic resistance to certain cytotoxic drugs such as cisplatin that is used normally as chemoprevention. An understanding of the role of mismatch repair genes in molecular signaling mechanism of apoptosis and its involvement in HNPCC needs attention for further work into this important area of cancer research, and this review article is intended to accomplish that goal of linkage of apoptosis with HNPCC. The current review was not intended to provide a comprehensive enumeration of the entire body of literature in the area of HNPCC or mismatch repair system or apoptosis; it is rather intended to focus primarily on the current state of knowledge of the role of mismatch repair proteins in molecular signaling mechanism of apoptosis as it relates to understanding of HNPCC.

Attenuation of tissue oxidative stress by dietary restriction in rats on simulated microgravity.

INTRODUCTION: Physiologic alterations caused by oxidative stress can be assessed by measuring tissue malondialdehyde (MDA) levels, a biomarker for oxidative stress. The goal of this study is to determine the consequences of a twenty percent caloric restriction on the increased oxidative stress documented in tissues from rats exposed to simulated microgravity. MATERIALS/METHODS: Three groups of male SD rats (N=6 in each group) were used: Group 1, control; Group 2, food restricted (20% less food than control); and Group 3, food restricted with HLS. Group 3 was suspended after one week on the HLS-restricted diet and maintained for 14 days. Tissues harvested on day 14 were measured for MDA levels. RESULTS: The body weight gain of Group 2 and Group 3 was reduced as compared to that of Group 1 ( p <0.05) with no significant changes in water intakes. MDA levels in Group 2 were not different from those of the control group and were elevated only in liver tissues (p<0.05). In Group 3, MDA levels in the heart, liver, brain, and testes were significantly elevated (p<0.05) compared to the levels of Groups 1 and 2. CONCLUSIONS: Food restriction alleviated tissue oxidative response in all tissues except for the liver. Excessive stress resulting from HLS appeared to have been minimized by dietary restriction in all tissues except for the heart, liver, brain, and testes.

Pressure hyperalgesia in hind limb suspended rats.

INTRODUCTION: Spaceflight and simulated microgravity often associate with pain and prediabetes. Streptozotocin (STZ)-induced moderate insulinopenia rat models of prediabetes result in pressure hyperalgesia. The current study was designed to determine whether or not simulated microgravity induced by hind limb suspension (HLS) in rats lead to insulinopenia and pressure hyperalgesia. METHODS: Adult male rats were divided into HLS (N = 20) and control, non-suspended (N = 16) groups, respectively. Bodyweight and hind limb pressure-pain withdrawal threshold (PPT) were measured at regular 2-5 d intervals for 7 d before and 12-13 d after HLS. RESULTS: Bodyweights and PPT of control and HLS animals measured on the day of suspension were not different. During the experiment, control rats gained 61 +/- 5 g, but maintained their PPT at the baseline level. Suspended rats gained 26 +/- 3 g of weight during the same time period and their PPT declined from 105 +/- 6 g to 84 +/- 6 g. Neither blood glucose nor pancreatic islet density and area were affected by HLS. However, the random plasma insulin of HLS rats was significantly lower than that of control animals (1.6 +/- 0.2 vs. 2.7 +/- 0.2 ng ml(-1)). DISCUSSION: The observed relationship between insulin and PPT levels in the HLS rats was similar to that observed in rats with STZ-induced insulinopenia. These data suggest that moderate insulinopenia may affect the rat's sensitivity to deep pressure directly, without affecting glucose homeostasis. In addition, our data suggest that HLS rats may develop peripheral neuropathy.

Parimal Chowdhury's work on smoking related pancreatic disorders.

Cigarette smoking is a known risk factor for the development of numerous diseases. The role of nicotine in the induction of pancreatic inflammation and pancreatic cancer as a result of cigarette smoking has been recognized and reported in the literature. The mechanism by which nicotine induces such pathologies is as yet unknown. An understanding of the proliferative potential of nicotine in primary and tumor cells of the pancreas will allow us to develop measures that will ultimately lead to intervention, prevention and treatment of these diseases. Studies show that nicotine can increase the cell numbers of cer-tain cancer cell lines, suggesting that exposure to nicotine can lead to the disruption of the dynamic balance between cell death and proliferation, which is required for normal functioning of cells. We hypothesize that nicotine induces oxidative stress in pancreatic acinar cells and thus contributes to this disruption. We have used the AR42J cell line in our study because of its stability as an immortal tumor cell line and its known physiological similarity to primary acinar cells. Our studies show that mitogen activated protein kinase signaling is induced by nicotine in AR42J cells, causing an increase in lipid peroxidation and a subsequent decrease in cell function. Our data suggest that exposure to nicotine induces oxidative stress, leading to cell injury and compromised function, thus implicating cigarette smoking as a plausible mechanism.

Effects of aminoguanidine on tissue oxidative stress induced by hindlimb unloading in rats.

We investigated the effects of hindlimb unloading (HLU) on malondialdehyde (MDA), a biomarker for oxidative stress, and glutathione (GSH) levels in tissues of rats. Aminoguanidine (AG), a nucleophilic hydralazine compound and an in vivo antioxidant against reactive oxygen species (ROS) and lipid peroxidation, was used to confirm the HLU-induced oxidative response. Three groups of rats were used: Group 1 was a loaded control group that was maintained on drinking water only; Groups 2 and 3 were hindlimb unloaded (HLU) groups that were maintained on drinking water and on AG in drinking water, respectively. The hindlimb unloaded rats maintained on tap water had significantly elevated MDA levels in 7 tissues (brain, lung, pancreas, kidney, intestine, heart, liver) when compared to the paired hindlimb loaded controls (p <0.05). In contrast, the hindlimb unloaded rats maintained on AG in drinking water had no increase in tissue MDA levels when compared to the loaded controls; moreover, their tissue MDA levels were significantly reduced from the HLU group on tap water (p <0.05). In HLU rats maintained on AG, there were no changes in tissue GSH levels with the exception of brain, where GSH levels were significantly reduced when compared to the other groups (p <0.05). In summary, HLU induced an oxidative response in rats and this response was reduced significantly by ingestion of AG. These results suggest the potential application of AG in the diet of astronauts living in a stressful environment.

A report of the Sixth Annual Meeting of the International Society for the Prevention of Tobacco Induced Diseases (ISPTID).

The Sixth meeting of the International Society for the Prevention of Tobacco Induced Diseases (ISPTiD) was held in Little Rock, Arkansas on November 2-4, 2007 and has brought together 140 participants, scientists and experts in this specialized field from 30 countries across the World. The central theme of the conference was the "Translational Approaches to the Prevention of Tobacco Induced Diseases". Discussions held during the three days meeting's sessions (including poster session and platform discussion) promoted a better understanding of the connection between tobacco use and associated medical and health consequences. The Sixth Annual meeting of ISPTiD served as another successful step toward decrease in the huge sociological and economical burden that the entire World is facing with this addiction. The proceedings of the meeting were published in the conference booklet, the ISPTiD global web site and Cancer Database abstract web site. Funds generated from this meeting helped in part to establish the society's Journal "Tobacco Induced Diseases "into the major scientific journal index PubMed database and BioMed Central. The meeting set the tone for next the Annual meeting in Kyoto, Japan for the year 2008 with the theme "Tobacco free future".

Mitogenic and functional responses by nicotine and hydrogen peroxide in AR42J cells: a comparative study.

The aim of the current study was to investigate the oxidative effects of nicotine by examining the mitogenic and functional responses in AR42J cells. As a control and for comparison, hydrogen peroxide (H2O2) was used as a source of known oxidative biomarker. Responses were examined by determining cell proliferation through the activation of ERK signaling, basal and CCK-stimulated cell function and measuring lipid peroxidation. AR42J cells have been exposed to either a non-cytotoxic dose of 20 muM H2O2 for 15 min or to 100 muM of nicotine for 3 min respectively. Nicotine and H2O2 at these dose and time intervals produced similar levels of malondialdyde (MDA) production and p-ERK1/2 activation. Immunofluorescence studies employing specific antibody to p-ERK1/2 confirmed the latter. Nicotine-induced increase in the proliferation of AR42J cells was significantly higher in comparison to H2O2 exposed cells. CCK-stimulated cell function induced by nicotine was significantly higher in AR42J cells as compared to the response by H2O2. These results suggest that nicotine- induced mitogenic and functional response in AR42J cells are associated with ERK signaling and increase in reactive oxygen species production. The data suggests that nicotine-induced mitogenic response in AR42J cells closely identifies the response induced by an oxidative biomarker.

A cell-based approach to study changes in the pancreas following nicotine exposure in an animal model of injury.

BACKGROUND: Cigarette smoking is a recognized risk factor for the induction of pancreatic diseases and is suspected to play a major role in the development of pancreatic cancer in smokers. MATERIALS AND METHODS: This study was designed to characterize the mechanisms of nicotine-induced injury to the pancreas. AR42Jcells, a stable mutant pancreatic tumor cell line, was chosen for the study because of its stability in culture media and also because of its known secretory capacity, which is like that of a normal pancreatic acinar cell. It is hypothesized that nicotine-induced effects on the pancreas are triggered by oxidative stress induced in pancreatic acinar cell via oxidative stress signaling pathways. RESULTS: The results from our study showed that, in vitro, nicotine induced generation of oxygen free radicals measured as malondialdehyde, an end product of lipid peroxidation. Treatment of AR42J cells with nicotine induced p-ERK 1/2 activation as confirmed by Western blot and immunofluorescence imaging of cytoplasmic localization of mitogen-activated protein kinase (MAPK) signals. Nicotine enhanced AR42J cell proliferation and cholecystokinin-stimulated amylase release in AR42J cells. These effects of nicotine were confirmed by simultaneous studies conducted on the same cells by hydrogen peroxide, a known oxidative biomarker. Allopurinol, a XOD inhibitor, suppressed these effects induced by nicotine and H(2)O(2) with the exception that cholecystokinin-stimulated amylase release by H(2)O(2) remained unaltered when AR42J cells were preincubated with allopurinol. These results suggest that nicotine-induced effects on pancreatic acinar cells were associated with generation of oxyradical mediated via the XOD pathway. The results have a direct impact on cell proliferation, MAPK signaling, and acinar cell function. CONCLUSION: We conclude that nicotine induces oxidative stress in pancreatic acinar cells and that these events trigger pathophysiological changes in the pancreas, leading to increased cell proliferation and injury.

L-carnitine influence on oxidative stress induced by hind limb unloading in adult rats.

INTRODUCTION: An improvement in the imbalance in the oxidant-antioxidant defense system would lessen the severity of any oxidative stress documented during or after spaceflight. In this study, we investigated the effects of a 14-d hind limb unloading (HLU) of rats on the formation of malondialdehyde (MDA), an oxidative biomarker and also an end-product of lipid peroxidation, in tissues and blood of rats. L-carnitine, a well-known enhancer of activities of the mitochondrial antioxidant system, was used to confirm the HLU-induced oxidative response. METHODS: Three groups of rats were used in the current study. Group 1 was a control group that was maintained on drinking water only; Groups 2 and 3 were unloaded HLU groups that were maintained on drinking water and on L-carnitine in drinking water, respectively. RESULTS: Our results showed that rats that were hind limb unloaded but maintained on water only showed enhanced levels of tissue MDA when compared with the paired hind limb loaded controls. Animals hind limb unloaded but maintained on L-carnitine in their drinking water had no increase in their tissue MDA levels when compared with the loaded controls, but their MDA levels were significantly reduced from the HLU group, p < 0.05. DISCUSSION AND CONCLUSIONS: These data indicate that HLU induced an oxidative response in rats and this response was absent in the presence of L-carnitine. The results of our study implicate the potential application of antioxidants as a useful dietary source in astronauts living in a stressful environment.

Pathophysiology of alcoholic pancreatitis: an overview.

Use of alcohol is a worldwide habit regardless of socio-economic background. Heavy alcohol consumption is a potential risk factor for induction of pancreatitis. The current review cites the updated literature on the alcohol metabolism, its effects on gastrointestinal and pancreatic function and in causing pancreatic injury, genetic predisposition of alcohol induced pancreatitis. Reports describing prospective mechanisms of action of alcohol activating the signal transduction pathways, induction of oxidative stress parameters through the development of animal models are being presented.

Nicotine as a mitogenic stimulus for pancreatic acinar cell proliferation.

Cell proliferation is an important process in life for growth of normal and cancer cells. The signal transduction pathways activated during this process are strictly regulated. This editorial focuses on the role of nicotine, a mitogen, in the induction of signaling pathways resulting in proliferation of pancreatic tumor cells and compares these events with those in normal acinar cells isolated from the rat pancreas. The data shows striking similarities between these two cellular systems. In addition, the editorial reviews very recent literature of the contribution of MAPK signaling in cell lines associated with human diseases. A prospective cellular model of nicotine induced activation of MAPK cascade is presented.

The genetics of nicotine dependence: relationship to pancreatic cancer.

Smoking of tobacco products continues to be a major cause of worldwide health problems. Epidemiological studies have shown that tobacco smoking is the greatest risk factor for the development of pancreatic cancer. Smokers who are able to quit smoking can reduce their risk of pancreatic cancer by nearly 50% within two years, however, their risk of developing pancreatic cancer remains higher than that of non-smokers for 10 years. Nicotine is the major psychoactive substance in tobacco, and is responsible for tobacco dependence and addiction. Recent evidence suggests that individuals have genetically based differences in their ability to metabolize nicotine, as well as genetic differences in the psychological reward pathways that may influence individual response to smoking initiation, dependence, addiction and cessation. Numerous associations have been reported between smoking behavior and genetic polymorphisms in genes that are responsible for nicotine metabolism. In addition, polymorphisms in genes that encode neurotransmitters and transporters that function in psychological reward pathways have been implicated in differences in smoking behavior. However, there is a large degree of between-study variability that demonstrates the need for larger, well-controlled case-control studies to identify target genes and deduce mechanisms that account for the genetic basis of inter-individual differences in smoking behavior. Understanding the genetic factors that increase susceptibility to tobacco addiction may result in more effective tobacco cessation programs which will, in turn, reduce the incidence of tobacco related disease, including pancreatic cancer.

Nanocluster model of photothermal assay: application for high-sensitive monitoring of nicotine-induced changes in metabolism, apoptosis, and necrosis at a cellular level.

This study evaluates the capability of a photothermal (PT) assay to monitor the impact of nicotine on pancreatic cancer cells (AR42J). The specific PT response is closely proportional to nicotine concentrations at concentration range 1 nM to 100 microM, while at high concentrations of nicotine ranging from 1 mM to 50 mM, PT response shows dramatic decrease. According to the theoretical model, the mechanism of the PT assay is associated with metabolic and apoptotic-related shrinking of local cellular absorbing nanoscale zones caused by increased local absorption at low nicotine doses, while high doses of nicotine lead to apoptotic release of absorbing component (cytochrome c) into the intracellular space, and necrotic swelling of organelles, thereby causing a decrease in local absorption. This model is verified with conventional imaging and with Annexin-V Propidium iodide kits. The PT assay, in addition to its high sensitivity (3 orders of magnitude better than conventional assay), shows the potential to distinguish between various functional states of cells that are associated with changes in metabolism, early and late stages of apoptosis, and necrosis. Comparison of PT responses of pancreatic tumor cells AR42J with isolated primary pancreatic acinar cells and HepG2 cells shows a universal nature of PT assay.