Mammalian aging is complex and incompletely understood. Although significant effort has been spent addressing the genetics or, more recently, the pharmacology of aging, the toxicology of aging has been relatively understudied. Just as an understanding of 'carcinogens' has proven crucial to modern cancer biology, an understanding of environmental toxicants that accelerate aging ('gerontogens') will inform gerontology. In this review, we discuss the evidence for the existence of mammalian gerontogens, as well as describe the biomarkers needed to measure the age-promoting activity of a given toxicant. We focus on the effects of putative gerontogens on the in vivo accumulation of senescent cells, a characteristic feature of aging that has a causal role in some age-associated phenotypes.
Carcinoma of the gastrointestinal tract is the most common internal malignancy affecting men and women in Western countries. Chronic intestinal inflammation, especially of the colon, is also a Western disease and correlates with a significantly increased risk of developing cancer. This has suggested that the immune processes involved in both conditions might share some common pathways. Indeed, there is increasing evidence that phosphatidylinositol 3-kinases (PI 3-kinases) are involved in both the pathogenesis of colorectal carcinoma and intestinal inflammation. Here, we discuss this rapidly progressing area of research, presenting evidence for a pivotal role of PI 3-kinase(s) in intestinal pathophysiology.
WENDEL Yarbrough and colleagues (University of North Carolina at Chapel Hill, NC, USA) have made advances towards the treatment of head and neck cancer. 3-D cell-culture models that imitate the real structure of head and neck epithelium were used as recipients of adenovirus-mediated gene delivery. Epithelial cells in a monolayer were easy to infect due to the presence of the human coxsackie and adenovirus receptor (hCAR). However, the group noted that expression of hCAR was most prevalent in undifferentiated dividing cells, particularly oropharyngeal tumor cells. This raises the prospect of adenoviral gene delivery to these tumor sites without affecting surrounding non-cancerous cells. Furthermore, such a system may prove useful in treating severe cellular dysplasia, a precancerous condition in which hCAR expression is maintained. Yarbrough commented, ‘theoretically, in people at high risk for cancer, adenoviral gene therapy would only infect the precancerous sites and leave the normal, well differentiated sites alone’. (AR).
The elucidation of whole-genome sequences is expected to have a revolutionary impact on the discovery of novel medicines. With the availability of complete genome sequences of more than 30 different species, the field of antimicrobial drug discovery has the opportunity to access a remarkable diversity of genomic information. In this review, I summarize how microbial genomics has changed strategies of drug discovery by applying bioinformatics, novel genetic approaches and genomics-based technologies, including analysis of gene expression using DNA microarrays.
The prion diseases, including Creutzfeldt–Jakob disease (CJD) and Gerstmann–Straussler–Scheinker disease (GSS) in humans, and bovine spongiform encephalopathy (BSE) in cattle, can exhibit inherited, infectious and sporadic presentations. Moreover, inherited forms of these diseases can be infectious. Obviously, infectious diseases imply an exogenous exposure to a pathogen, whereas inherited diseases are associated with alterations to genomic DNA. To unify these apparently conflicting observations, Prusiner proposed that an endogenous prion protein was the infectious agent, and that mutated forms of this protein were responsible for inherited diseases. Subsequent work has identified the genomic sequence of the prion protein, the nature of the mutations associated with inherited disease, and the conformational distinction between the normal cellular isoform of the prion protein (PrPC) and its disease causing counterpart (PrPSc) (Reviewed in Ref. 1).
Psoriasis manifests between the ages of 20 and 40 and is characterized by plaque-like hyperproliferative skin lesions, particularly at sites of trauma. It affects around 1–2% of the population and can be associated with other inflammatory diseases. Disease can be triggered by climate, stress and, of course, genetic factors. Like many other complex genetic diseases, no specific susceptibility mutations have been identified as yet, although linkage to a number chromosome regions has been demonstrated, such as 17q25. The strongest genetic association for psoriasis is with the human leukocyte antigen (HLA) gene cluster on 6p21, and specifically linkage with the HLA-Cw6 allele. Genomic sequence of the chromosome region harbouring the psoriasis-susceptibility locus PSORS1 is available, which should greatly facilitate the identification of disease genes. One such candidate, CORNEO-DESMOSIN, is genetically linked to PSORS1 (mapping 160 kb distal to HLA-C) and is expressed in the skin with a proposed role in keratinocyte differentiation and desquamation. However, Nair et al.1 Nair R.P. et al. Localisation of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C. Am. J. Hum. Genet. 2000; 66: 1833-1844 Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar now provide convincing evidence to exclude HLA-C and CORNEODESMOSIN as candidates for PSORS1.
Finding inhibitors of the first step of the amyloid cascade, A beta (42) generation, is a major goal of Alzheimer's disease drug development. Two target protease activities, beta-and gamma-secretase, were detected more than 10 years ago but progress in this area has been slow because the enzymes were not identified. Using an expression cloning strategy we have identified a novel membrane bound aspartic protease, BACE1, as beta-secretase. The enzyme has been characterized in detail. The X-ray crystal structure, which is critical for rational inhibitor design, has been solved and shown to be similar to that of other pepsin family members. Our recent knockout studies show that BACE1 is critical for A beta generation, but the knockout mice show an otherwise normal phenotype, raising the possibility that therapeutic BACE1 inhibition could be accomplished without major mechanism based toxicity. Target-mediated toxicity of beta-secretase inhibition cannot be ruled out, however, as long as the major substrates of this enzyme are unknown. Although various peptidic beta-secretase inhibitors have been published, the key challenge now is the generation of more drug-like compounds that could be developed for therapeutic purposes. The focus of this review is progress in the beta-secretase field from the identification of the enzyme in 1999 to the most recent publications.
Systemic lupus erythematosus is an autoimmune disorder that predominantly affects women during the childbearing years. Clinically, major organ systems are affected, including the skin, kidneys and nervous system. Genetic, hormonal, environmental and immunoregulatory factors contribute to the highly variable expression of the disease. Impaired cellular and humoral immune responses reflect disordered biochemical and molecular functions that might be determined genetically. Enhanced understanding of these molecular abnormalities should enable development of new, effective therapeutic agents in the near future.
The use of immunosuppressive agents in the treatment of transplant rejection and autoimmune disorders is gaining momentum, with significant improvements of both graft and patient survival. The individual response to drugs, however, is variable and unexpected toxicity, or impaired activity might be seen, as a result of molecular determinants that eventually dictate how the individual will respond to immunosuppressive agents. This review addresses a number of issues related to pharmacogenetics, and discusses how this approach might be used to improve the clinical efficacy and tolerability of therapeutic options for the management of organ transplantation and autoimmune disorders in the next decade.
Biological agents that inhibit the activity of proinflammatory cytokines are being investigated for use in the treatment of rheumatoid arthritis, Thus far, two of these agents, both of which neutralize tumor necrosis factor alpha (TNF-alpha), have received US Food and Drug Administration approval for the treatment of the disease, Etanercept is a bioengineered fusion protein of the p75 soluble TNF receptor, and infliximab is a chimeric monoclonal antibody to TNF-alpha, Other agents that target proinflammatory cytokines are also being developed. By allowing earlier treatment and better-tolerated long-term therapy, biologics might help slow or prevent disease progression and joint destruction.
Gene therapy vectors based on the adeno-associated virus (AAV) are being developed for a widening variety of therapeutic applications. Enthusiasm for AAV is due, not only to the relative safety of these vectors, but also to advances in understanding of the unique biology of this virus. This review examines a number of long-standing concerns regarding the utility of AAV for gene transfer in light of many new insights into the biology, immunology and production of AAV.
Colorectal cancer is the second most common cause of cancer mortality in Western countries. Gene therapy represents a novel approach to the treatment of colorectal cancer, and this review addresses the current strategies and ongoing clinical trials, including gene correction, immunomodulatory approaches and virus-directed enzyme-prodrug systems. Although the pre-clinical results for these strategies have been encouraging, clinical trials have not yet reflected these data. However, gene therapy for colorectal cancer is still in the early stages of development, and its potential, particularly in combination with conventional cancer therapies, warrants further investigation.
Eosinophils have been implicated in a broad range of diseases, notably allergic conditions (for example, asthma, rhinitis and atopic dermatitis) and other inflammatory disorders (for example, inflammatory bowel disease, eosinophilic gastroenteritis and pneumonia). These disease states are characterized by an accumulation of eosinophils in tissues. Severe tissue damage ensues as eosinophils release their highly cytotoxic granular proteins. Defining the mechanisms that control recruitment of eosinophils to tissues is fundamental to understanding these disease processes and provides targets for novel drug therapy. An important discovery in this context was the identification of an eosinophil-specific chemoattractant, eotaxin. Over the past six years there has been intensive investigation into the biological effects of eotaxin and its role in specific disease processes and this is the subject of this review.
Growing evidence that adenosine mediates some of the damage caused in stroke raises the possibility that blocking the receptors pharmacologically in the hours following stroke, could spare patients some of the resulting disabilities. A knockout mouse created by Jiang-Fan Chen, Michael Schwarzchild and colleagues (Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA) 1 Chen J-F. et al. A2A adnosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J. Neurosci. 1999; 19: 9192-9200 Crossref PubMed Google Scholar could shed light on the mechanisms by which adenosine has these effects.
Neuronal Plasticity: the key to stroke recovery
Alzheimer’s disease is characterized by the presence of neurofibrillary tangles and senile neuritic plaques in the brain. Tangles are aggregates of paired helical filaments composed of the microtubule-associated protein, tau, in a hyperphosphorylated state. Senile plaques have a core of amyloid β-peptide derived by proteolysis of the amyloid precursor protein. A major hurdle in defining the pathogenic mechanisms in Alzheimer’s disease is to understand how both amyloid β-peptide deposition and paired helical filament formation are biochemically linked. Recent genetic discoveries provide some clues, suggesting that components of two developmentally important signalling pathways, Notch and wingless, or the vertebrate homologue of wingless, Wnt, are involved.
This year Trends will celebrate a quarter-century of publishing reviews as Trends in Biochemical Sciences reaches its ‘25th birthday’. This event will be highlighted with a Trends special issue in December that will review the most significant technological advances of the past 25 years written by pioneers in their respective fields. Each Trends journal will contribute to provide an outstanding spectrum of life sciences reviews in a single issue. Molecular Medicine Today was launched in 1995 as a key addition to the Trends collection of monthly review journals. It provides a forum for the explanation and discussion of ideas and issues that relate to the multidisciplinary field of molecular medicine. Our audience includes researchers across the life sciences, clinicians and clinical scientists who all use it to keep up to date on the latest advances in this rapidly progressing area. Last month, Robert C. Stein and Michael D. Waterfield provided an authoritative review of the phosphoinositide 3-kinases (PI 3-kinases) as targets for drug development to fight cancer and inflammatory diseases. In this month’s issue, Martin Citron describes the secretases as targets for combating Alzheimer’s disease, and Erich E. Wanker discusses the potential therapeutic strategies for treating Parkinson’s disease and Huntington’s disease. On page 398, Yoel Kloog and Adrienne D. Cox review the potential of Ras inhibitors for cancer therapeutics. Also in this month’s issue is a notable review by Warren J. Leonard, on page 403, documenting the rapid progress from identification of the gene mutation for X-linked severe combined immunodeficiency to development of gene therapy in only seven years. This is a remarkable achievement for the gene therapy community and brings renewed hope for long-term success. The historic publication of the ‘working draft’ of the human genome also marks unprecedented opportunities for understanding the molecular basis of human disease for therapeutic applications. Over the past 25 years the Trends family of journals have developed along with the changing fields they represent so we are delighted to announce that from January 2001, Molecular Medicine Today will become Trends in Molecular Medicine. We would like to thank our distinguished Advisory Editorial Board for their contribution and we look forward to future endeavours. As our new name suggests, Trends in Molecular Medicine will reflect the continued evolution of research in molecular medicine. Trends in Molecular Medicine will continue to publish the highest quality, peer-reviewed articles written by leaders in the field, providing the broadest and most direct coverage of life sciences research as it moves from the bench towards clinical application. Trends in Molecular Medicine will feature more reviews, provocative opinion articles, topical news and comment, meeting reports, book reviews and insightful commentary on innovative papers from the primary literature. Milestones in the development of Molecular Medicine Today have included online access (via the BioMedNet gateway http://www.bmn.com) to full-text articles for our subscribers since May 1999 and the addition of a Disease Model section launched in June 1999. We have welcomed your comments on what you have wanted to read in Molecular Medicine Today and we look forward to your suggestions for what you would like to see more of in Trends in Molecular Medicine. We have appreciated the loyalty of our readers and authors during the past five years and we will need your support as Trends in Molecular Medicine continues its development. In the first year after the title change, Trends in Molecular Medicine will be listed in the ISI Journal Citation Report¿ without an impact factor, due to the article count for the two preceding years (used for impact factor calculations) being zero. Molecular Medicine Today will remain listed with a normal impact factor. One year later, the Journal Citation Report® will list separate impact factors for both titles. In this second year, the impact factor for Trends in Molecular Medicine may be lower than expected, as the article count includes only younger articles. Similarly, the impact factor for Molecular Medicine Today may be higher than expected as it is based upon only older articles. It is possible to calculate a unified impact factor, by totalling the citations to the two previous years and dividing that by the sum of the article counts for the two titles. In the third year after a title change, Molecular Medicine Today will no longer be listed in the ISI Journal Citation Report®.
