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 certain 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 bynicotine 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.

Distribution of ^3H—nicotine in Rat Tissues Under the Influence of Simulated Microgravity

Rat tail suspension offers a useful model to reproduce physiologic responses to weightlessness.The present study was conducted in the head-down-tilt(HDT) rat model to assess changes in metabolism of body tissues employing 3H-nicotine. Twelve male rats were used in the study. Half of the rats were tail suspended at 30°for two weeks on a 12/12 light/dark cycle. During this period,body weight, food and fluid intakes were measured. At term, animals were anesthetized and injected IV withe a solution contaming 4 microuries of micotine. After 90 min the animals were sacrificed, exsanguinated and tissues (brain,blood,trachea,salivary gland,lung,heart,esophagus,spleen, kidneys and testes) were harvested. The distribution of 3H-nicotine per gram of each tissue was determinded and ealeulated as percent of total injected radioactivity. Final body weights of suspended ammals were significantly (P < 0.0 5) lower than those of eontrols(309±21 vs 350±11g). 3HNicotine waw retained in greatest amounts by the kindneys, followed inorder by salivary glands, spleen, and gastrointestinal tissues. compared to non-suspended control, the tissue retention of nicotine in suspended animals was decreased in the following tissues:esphyagus (25 %), aorta (25%). fundus (25%), trachea (22%), adrenals (18%), spleen (17 %), and pancreas (12 %). The decreased retention of mcotine in tissues from suspended animals may be indicative of the fluid shifts and changes in blood flow to those tissue beds. The lack of differnces in nicotine retention in liver and kidney between control and suspended groups may implicate a normal metabolic function of these organs even under simulated weightlessness.

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 casecontrol studies to identify target genes and deduce mechanisms that account for the genetic basis of interindividual 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.

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.

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.