Showing papers in "The Biomedical & Life Sciences Collection in 2007"

Sjogren's Syndrome: Autoimmune Epithelitis

Abstract: Sjogren's syndrome (SS), the ideal model to study autoimmunity and lymphoid malignancy, is a common chronic disease which in the last 30 years has been studied extensively on clinical and pathophysiological grounds. Clinical studies regarding kidney disease in SS patients have shown that the predominate lesion is interstitial nephritis which produces tubular dysfunction. Studies on lung involvement have previously indicated that one-fourth of SS patients suffer from subclinical, interstitial lung disease. Reevaluation, however, of the pulmonary disease, using functional, radiologic (including CT-scan), and histopathologic studies, revealed that the lesion starts peribronchially. Finally, evaluation of liver disease in SS patients revealed that this consists of a pericholangeal round-cell infiltrate resembling the early lesion of primary biliary cirrhosis. These clinical studies suggest that the majority of extraglandular manifestations of SS are due to the attraction of lymphocytes by different epithelial tissues. Studies of the epithelial cells of minor salivary glands from SS patients have shown that these inappropriately and selectively express HLA class II molecules and the protooncogene c-myc. Evaluation of cytokines in the minor salivary glands from these patients, by in situ hybridization, revealed that the mRNA of the proinflammatory cytokines IL-1 and IL-6 also comes from the epithelial cells. Finally, proviral DNA is incorporated in the DNA of epithelial cells. On the basis of these clinical and basic observations, we suggest that the major suffering cell in SS patients is the epithelium and thus we propose this descriptive term "autoimmune epithelitis" instead of "Sjogren's syndrome.

p53 and apoptosis

Abstract: One of the several biological functions attributed to p53 is the ability to induce apoptotic cell suicide. It has become clear that this apoptotic activity of p53 is central to its role as a tumor suppressor. A summary of current knowledge concerning the mechanisms of p53-mediated apoptosis is presented. The pivotal 'choice' between p53-induced viable growth arrest and apoptosis is discussed.

Genetic Conflicts in Human Pregnancy

Abstract: Pregnancy has commonly been viewed as a cooperative interaction between a mother and her fetus. The effects of natural selection on genes expressed in fetuses, however, may be opposed by the effects of natural selection on genes expressed in mothers. In this sense, a genetic conflict can be said to exist between maternal and fetal genes. Fetal genes will be selected to increase the transfer of nutrients to their fetus, and maternal genes will be selected to limit transfers in excess of some maternal optimum. Thus a process of evolutionary escalation is predicted in which fetal actions are opposed by maternal countermeasures. The phenomenon of genomic imprinting means that a similar conflict exists within fetal cells between genes that are expressed when maternally derived, and genes that are expressed when paternally derived. During implantation, fetally derived cells (trophoblast) invade the maternal endometrium and remodel the endometrial spiral arteries into low-resistance vessels that are unable to constrict. This invasion has three consequences. First, the fetus gains direct access to its mother's arterial blood. Therefore, a mother cannot reduce the nutrient content of blood reaching the placenta without reducing the nutrient supply to her own tissues. Second, the volume of blood reaching the placenta becomes largely independent of control by the local maternal vasculature. Third, the placenta is able to release hormones and other substances directly into the maternal circulation. Placental hormones, including human chorionic gonadotropin (hCG) and human placental lactogen (hPL), are predicted to manipulate maternal physiology for fetal benefit. For example, hPL is proposed to act on maternal prolactin receptors to increase maternal resistance to insulin. If unopposed, the effect of hPL would be to maintain higher blood glucose levels for longer periods after meals. This action, however, is countered by increased maternal production of insulin. Gestational diabetes develops if the mother is unable to mount an adequate response to fetal manipulation. Similarly, fetal genes are predicted to enhance the flow of maternal blood through the placenta by increasing maternal blood pressure. Preeclampsia can be interpreted as an attempt by a poorly nourished fetus to increase its supply of nutrients by increasing the resistance of its mother's peripheral circulation.

Randomization in clinical trials

Abstract: Randomization in clinical trials : , Randomization in clinical trials : , کتابخانه دیجیتالی دانشگاه علوم پزشکی و خدمات درمانی شهید بهشتی

Protein aggregation, metals and oxidative stress in neurodegenerative diseases

Abstract: There is clear evidence implicating oxidative stress in the pathology of many different neurodegenerative diseases. ROS (reactive oxygen species) are the primary mediators of oxidative stress and many of the aggregating proteins and peptides associated with neurodegenerative disease can generate hydrogen peroxide, a key ROS, apparently through interactions with redox-active metal ions. Our recent results suggest that ROS are generated during the very early stages of protein aggregation, when protofibrils or soluble oligomers are present, but in the absence of mature amyloid fibrils. The generation of ROS during early-stage protein aggregation may be a common, fundamental molecular mechanism underlying the pathogenesis of oxidative damage, neurodegeneration and cell death in several different neurodegenerative diseases. Drugs that specifically target this process could be useful in the future therapy of these diseases.

Targeting Apoptosis Pathways in Cancer Therapy

Abstract: Apoptosis, or programmed cell death, is a mechanism by which cells undergo death to control cell proliferation or in response to DNA damage. The understanding of apoptosis has provided the basis for novel targeted therapies that can induce death in cancer cells or sensitize them to established cytotoxic agents and radiation therapy. These novel agents include those targeting the extrinsic pathway such as tumor necrosis factor‐related apoptosis‐inducing ligand receptor 1, and those targeting the intrinsic Bcl‐2 family pathway such as antisense bcl‐2 oligonucleotides. Many pathways and proteins control the apoptosis machinery. Examples include p53, the nuclear factor kappa B, the phosphatidylinositol 3 kinase pathway, and the ubiquitin/proteosome pathway. These can be targeted by specific modulators such as bortezomib, and mammalian target of rapamycin inhibitors such as CCI‐779 and RAD 001. Because these pathways may be preferentially altered in tumor cells, there is potential for a selective effect in tumors sparing normal tissue. This article reviews the current understanding of the apoptotic pathways, including the extrinsic (cytoplasmic) and intrinsic (mitochondrial) pathways, and the agents being developed to target these pathways.

Targeting apoptosis pathways in cancer therapy

Abstract: Killing of tumor cells by anticancer therapies commonly used in the treatment of cancer, e.g. chemotherapy, gamma-irradiation, immunotherapy or suicide gene therapy, is predominantly mediated by triggering apoptosis, the cell's intrinsic death program. Accordingly, defects in apoptosis pathways can result in cancer resistance to current treatment approaches. Understanding the molecular mechanisms that regulate cell death programs including apoptosis, and how resistant forms of cancer evade apoptotic events, may provide novel opportunities for cancer drug development.

Vascular cell signaling by membrane estrogen receptors

Abstract: There is substantial interest in the effects of estrogen on the vascular wall, due to the marked gender difference in the incidence of clinically apparent coronary heart disease (CHD), when comparing premenopausal women with age-matched males. Recent randomized clinical trials unexpectedly failed to demonstrate a hormone replacement therapy (HRT) benefit for CHD secondary or primary prevention in postmenopausal women. There are several possible explanations for these findings, which have created a conundrum in light of the numerous potentially beneficial vascular effects of estrogen demonstrated at the cellular, molecular, and even animal model level. Clinical trials are ongoing, and the dissection of molecular pathways continues. Although estrogen receptors (ERs) are traditionally defined as ligand-activated transcriptional activators or repressors, a phenomenon certainly involved in some of estrogen's beneficial effects on vascular cells, we and others have recently demonstrated the presence of membrane-associated ERs in endothelial cells (EC), and that engagement of this subset of receptors may also contribute to the favorable molecular profile of the endothelium. In this review, we describe evidence for membrane-localized ERs in EC. We discuss features of their membrane targeting, and how they may differ from classical ERs. We also describe the rapid assembly of a membrane-associated molecular complex, comprised of ER, c-Src and the regulatory unit of phosphatidylinositol 3-kinase (PI3K), p85, in response to estrogen. Finally, we describe how this complex triggers sequential enzyme activation, involving endothelial nitric oxide synthase (eNOS), and consequent enhanced basal release of NO, a key modulator of vascular tone and 'healthy' blood vessels.

Epigenetics: a historical overview

Abstract: In the first half of the twentieth century, developmental biology and genetics were separate disciplines. The word epigenetics was coined by Waddington to link the two fields. Epigenetics could be broadly defined as the sum of all those mechanisms necessary for the unfolding of the genetic programme for development. Several decades later specific mechanisms were proposed in which information was superimposed on DNA sequences. In particular, it was suggested that 5-methyl cytosine had a role in controlling gene expression, and also that the pattern of methylation was heritable. These predictions are now supported by a large body of evidence which shows that methylation is strongly associated with gene silencing in a variety of biological contexts. There are now also many examples of epigenetic inheritance through the germ line There are several other important epigenetic mechanisms involving chromatin and histone modifications, and also the expanding field of regulatory RNAs. The human epigenome project will unravel the pattern of DNA methylation in different tissues, and will this determine whether the regulation of gene expression is at the level of DNA or chromatin, or both.

Vitamin D and prostate cancer

Abstract: An analysis of the rising incidence and mortality rate of prostate cancer reveals the extraordinary importance of this disease in the world. Adenocarcinoma of the prostate is the most common cancer diagnosed in American males, reaching an estimated incidence of 32%, with 200,000 cases of newly diagnosed cancer cases expected in 1994.1 In addition, clinically inapparent prostate cancer is an extremely common finding. Over the age of 80, subclinical prostate cancer is found in approximately 60% of all men.2 Overall, it is estimated that there are 11 million men in the U.S. with lesions within their prostates that are histologically identifiable as cancer.3 Mortality from prostate cancer represents a considerable problem. It is expected that prostate cancer will account for 13% (38,000 cases) of male cancer deaths in 1994.1 This makes prostate cancer the second leading cause of cancer-related death in U.S. men after lung cancer. Mortality rates from prostate cancer appear to be on the rise. From 1970 to 1990 the age-adjusted mortality rate from prostate cancer increased approximately 7 % among U.S. caucasians. Since prostate cancer rates increase with age, as the longevity of the population increases, it is projected that prostate cancer will become the leading cause of cancer and cancer death in men. These observations demonstrate that prostate cancer is one of the major adverse factors in the health of the male population in the United States and for that matter, in the rest of the world as well.

Epidemiology of obesity

Abstract: The prevalence of obesity is increasing at an alarming rate in many parts of the world. In White populations living in the west and north of Europe, Australia, and the United States, the prevalence of obesity is similarly high in men and women. In countries with relatively low gross national product, such as those in Central and Eastern Europe, Asia, Latin-America, and Africa, the prevalence is 1.5 to 2 times higher among women than among men. Within affluent societies, the rates of obesity seem to be more common among women at older ages (65 years) and in groups with relatively low socioeconomic status. It can be tentatively concluded that obesity is particularly common in women living in relatively poor conditions.

Endocrinology of parturition

Abstract: Reproductive success is critical for survival of the species. The timely onset of labor and delivery is an important determinant of perinatal outcome. Both preterm birth (defined as delivery before 37 weeks' gestation) and post-term pregnancy (defined as pregnancy continuing beyond 42 weeks) are associated with a significant increase in perinatal morbidity and mortality. The factors responsible for the timing of labor in the human are complex and, as yet, are not completely understood. This article reviews the current understanding of the parturition cascade responsible for the spontaneous onset of labor at term and discusses preterm labor and post-term pregnancy.

The role of chaperones in Parkinson's disease

Abstract: The etiologies of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, polyglutamine diseases, or prion diseases may be diverse; however, aberrations in protein folding, processing, and/or degradation are common features of these entities, implying a role of quality control systems, such as molecular chaperones and the ubiquitin-proteasome pathway. There is substantial evidence for a causal role of protein misfolding in the pathogenic process coming from neuropathology, genetics, animal modeling, and biophysics. The presence of protein aggregates in all neurodegenerative diseases gave rise to the hypothesis that protein aggregates, be it intracellular or extracellular deposits, may perturb the cellular homeostasis and disintegrate neuronal function (Table 1). More recently, however, an increasing number of studies have indicated that protein aggregates are not toxic per se and might even serve a protective role by sequestering misfolded proteins. Specifically, experimental models of polyglutamine diseases, Alzheimer's disease, and Parkinson's disease revealed that the appearance of aggregates can be dissociated from neuronal toxicity, while misfolded monomers or oligomeric intermediates seem to be the toxic species. The unique features of molecular chaperones to assist in the folding of nascent proteins and to prevent stress-induced misfolding was the rationale to exploit their effects in different models of neurodegenerative diseases. This chapter concentrates on two neurodegenerative diseases, Parkinson's disease and prion diseases, with a special focus on protein misfolding and a possible role of molecular chaperones.

Nuclear Organization and Gene Expression

Abstract: In actively transcribing cells, factors involved in pre-mRNA splicing localize in a speckled pattern at the fluorescence microscopic level. The speckled pattern corresponds to interchromatin granule clusters and perichromatin fibrils at the electron microscopic level. Based upon [3H]uridine incorporation studies transcription is thought to occur at the perichromatin fibrils and not within interchromatin granule clusters. We have shown that upon inhibition of RNA polymerase II transcription or pre-mRNA splicing, splicing factors redistribute and preferentially localize to interchromatin granule clusters, which become larger and more uniform in shape. Introduction of exogenous DNA templates into the cell nucleus results in a recruitment of splicing factors to the new sites of transcription. These data suggest that splicing factors are localized at storage and/or reassembly sites (interchromatin granule clusters) and are recruited to active sites of transcription (perichromatin fibrils). Furthermore, these data demonstrate that the speckled localization of pre-mRNA splicing factors is a reflection of the transcriptional and pre-mRNA splicing activities of the cell.