Current Molecular Medicine

ISSN: 1566-5240

Current Molecular Medicine
Volume 6, Number 3, May 2006

Contents

From Gut Homeostasis to Cancer Pp. 275-289
Freddy Radtke, Hans Clevers and Orbicia Riccio
[Abstract]


Lymphoma and the Control of B Cell Growth and Differentiation Pp. 291-308
Lixin Rui and Christopher C. Goodnow
[Abstract]


Malaria: Therapy, Genes and Vaccines Pp, 309-326
Peter K. Chiang, Janusz M. Bujnicki, Xinzhuan Su and David E. Lanar
[Abstract]


Toll-Like Receptors and Corneal Innate Immunity Pp. 327-337
Ashok Kumar and Fu-Shin X. Yu
[Abstract]


Small RNAs and Non-Small Cell Lung Cancer Pp. 339-349
Alex W. Tong
[Abstract]


TAGE (Toxic AGEs) Theory in Diabetic Complications Pp. 351-358
Takashi Sato, Mina Iwaki, Noriko Shimogaito, Xuegang Wu, Sho ichi Yamagishi and Masayoshi Takeuchi
[Abstract]




Abstracts

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From Gut Homeostasis to Cancer
Freddy Radtke, Hans Clevers and Orbicia Riccio

The mammalian intestine has one of the highest turnover rates in the body. The intestinal epithelium is completely renewed in less than a week. It is divided into spatially distinct compartments in the form of finger-like projections and invaginations that are dedicated to specific functions. Intestinal cells are constantly produced from a stem cell reservoir that gives rise to proliferating transient amplifying cells, which subsequently differentiate and migrate to the correct compartment before dying after having fulfilled their physiological function. In recent years, a substantial body of evidence has accumulated to support the concept that signaling pathways known to be crucial for embryonic development of multiple organisms play a critical role in tightly regulating and controlling the self-renewing process of the intestine. Moreover, the same pathways appear to be deregulated in several hereditary and sporadic colorectal cancer syndromes due to activating and/or inactivating mutations of key components of such pathways.

In this review we discuss recent findings demonstrating that differentiation and homeostasis of the intestine are controlled by developmental pathways such as Wnt, Notch, TGF-β and Hedgehog, and illustrate how their deregulation contributes to intestinal neoplasia.


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Lymphoma and the Control of B Cell Growth and Differentiation P
Lixin Rui and Christopher C. Goodnow

It is now widely accepted that lymphomagenesis is a multistep transformation process. A number of genetic changes and environmental and infectious factors contributing to the development and malignant progression of B-cell lymphoproliferative disorders are well documented. Reciprocal chromosomal translocations involving the immunoglobulin loci are a hallmark of most mature B cell lymphomas and lead to dysregulated expression of proto-oncogenes (c-myc) important for cell proliferation or genes involved in cell cycle progression (cyclin D1), differentiation block (bcl-6, PAX5) and cell survival (bcl-2, NF-κB). In addition, genetic alterations that inactivate tumor suppressor genes (p53, p16) have been frequently detected in some lymphoma tissues. Many of these genes are normally regulated by signals from the B cell antigen receptor. The high prevalence of bacterial and viral infection in lymphoma patients supports the hypothesis that infectious agents may play a contributory role in the development and evolution of B cell lymphoproliferative disorders by either directly inducing polyclonal B cell hyperactivation (EBV, HCV), or providing a chronic antigenic stimulus (EBV, HCV, HBV, H. pylori), or mimicking B cell antigen receptor signaling (EBV, HCV, HHV8), although whether these are causative factors or they are secondary to genetic changes in lymphomagenesis remains to be defined. Stimulatory signals from reactive T cells, local cytokines and growth factors can also contribute, to some extent, to the progression of transformation. Modulation of B cell antigen receptor signaling therefore emerges as a potentially powerful strategy for controlling the growth of certain B cell lymphomas.


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Malaria: Therapy, Genes and Vaccines
Peter K. Chiang, Janusz M. Bujnicki, Xinzhuan Su and David E. Lanar

Malaria kills over 3,000 children each day. Modern molecular and biochemical approaches are being used to help understand and control Plasmodium falciparum, the parasite that causes this deadly disease. New drugs are being invented for both chemoprophylaxis and therapeutic treatments and their use is discussed along side that of the more commonly used treatments. Classical genetic crosses coupled with molecular analysis of gene loci are use to explain the genetics behind the development of specific drug resistances that the parasites have naturally developed. Rapid advances in DNA sequencing techniques have allowed the compete sequencing of the P. falciparum and several other rodent malaria parasite genomes. Proteomics and computational analysis of these vast databanks are being used to model and investigate the three-dimensional structure of many key malaria proteins in an attempt to facilitate drug design. Recombinant protein expression in bacteria and yeast coupled with cGMP purification technologies and conditions have lead to the recent availability of several dozen malaria protein antigens for human-use Phase I and Phase II vaccine trials. Drug companies, private foundations, and key government agencies have contributed to the coordinated efforts needed to test these antigens, adjuvants and delivery methods in an effort to find an effective malaria vaccine that will prevent infection and disease.


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Toll-Like Receptors and Corneal Innate Immunity
Ashok Kumar and Fu-Shin X. Yu

The ocular surface is constantly exposed to a wide array of microorganisms. The ability of the cornea to recognize pathogens as foreign and eliminate them is critical to retain its transparency, hence preservation of sight. In the eye, as in other parts of the body, the early response against invading pathogens is provided by innate immunity. Corneal innate immune system uses a series of pattern recognition receptors to detect the presence of pathogens thus allowing for rapid host defense responses to invading microbes. A key component of such receptors is the "Toll-like receptors" (TLRs), which have come to occupy the center stage in innate immunity against invading pathogens. An increasing number of studies have shown that TLRs are expressed by a variety of tissues and cells of the eye and play an important role in ocular defense against microbial infection. Here in this review we summarize the current knowledge about TLR expression in human eye with main emphasis on the cornea, and discuss the future directions of the field.


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Small RNAs and Non-Small Cell Lung Cancer
Alex W. Tong

Patients with non-small cell lung cancer (NSCLC) are commonly diagnosed with advanced disease and have limited therapeutic options. Experimental treatment approaches including small molecule targeted therapeutics, gene modified tumor vaccines, and viral-based gene therapy have induced tumor regression in a small proportion of patients, suggesting that advanced NSCLC is susceptible to molecular perturbations. RNA interference (RNAi) has generated considerable excitement as a potential cancer therapeutic application. RNAi is the process by which small, double stranded RNA molecules (small interfering RNA, or siRNA) can initiate sequence-specific, post-transcriptional gene silencing (PTGS). Cancer growth inhibition was attained through siRNA-knockdown of unique or overexpressed cancer oncogenetic messages that are relevant to NSCLC pathophysiology. As with other loss-of-function cancer gene therapy approaches, clinical efficacy of siRNA depends largely on the extent of cell target coverage at the locoregional and/or systemic level. Cationic liposomes as well as viral vectors have been used successfully for siRNA delivery. However, viral delivery may have more immediate relevance due to its wider clinical acceptance in the cancer gene therapy arena. We advocate the use of conditional replicative, oncolytic adenovirus for siRNA delivery, which offers potential benefits of restricted and renewable siRNA expression within the tumor microenvironment, and an additive anti-tumor outcome through viral oncolysis and siRNA-mediated oncogene-silencing, which we have demonstrated with the A549 NSCLC cell line. Several oncolytic adenoviral constructs are potentially applicable clinical platforms with proven infectivity and safety, which are feasible also for the delivery of microRNAs (miRNA), a recently discovered group of endogenous, small RNA with PTGS activity that is downregulated in lung cancer.


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TAGE (Toxic AGEs) Theory in Diabetic Complications
Takashi Sato, Mina Iwaki, Noriko Shimogaito, Xuegang Wu, Sho ichi Yamagishi and Masayoshi Takeuchi

Diabetic complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis. Chronic hyperglycemia is initially involved in the pathogenesis of diabetic micro- and macro-vascular complications via various metabolic derangements. High glucose increased production of various types of advanced glycation end-products (AGEs). Recently, we found that glyceraldehyde-derived AGEs (AGE-2) play an important role in the pathogenesis of angiopathy in diabetic patients. There is considerable interest in receptor for AGEs (RAGE) found on many cell types, particularly those affected in diabetes. Recent studies suggest that interaction of AGE-2 (predominantly structure of toxic AGEs; TAGE) with RAGE alters intracellular signaling, gene expression, release of pro-inflamatory molecules and production of reactive oxygen species (ROS) that contribute towards the pathology of diabetic complications. We propose three pathways for the in vivo formation of AGE-2 precursor, glyceraldehyde, such as i) glycolytic pathway, ii) polyol pathway, and iii) fructose metabolic pathway. Glyceraldehyde can be transported or can leak passively across the plasma membrane. It can react non-enzymatically with proteins to lead to accelerated formation of TAGE at both intracellularly and extracellularly. In this review, we discuss the molecular mechanisms of diabetic complications, especially focusing on toxic AGEs (TAGE) and their receptor (RAGE) system.