Current Pharmaceutical Design - Volume 12, Issue 19, 2006

Prostanoids and cytokines are secreted or cell-surface associated effector molecules, which mediate cell-to-cell communication and regulate complex biological processes in health and disease. Some of these molecules are synthesized by cells having highly specialized functions (such as cells of the endocrine system), but most are ubiquitously expressed in more than one cell type or tissue. Originally, such regulatory molecules involved in inflammation or immunity were termed cytokines, as opposed to mediators of cell growth and movement, which were named growth factors and chemokines, respectively. Today this distinction does not exist as all these "functional" categories essentially fall into one large family of cytokines. More than 100 cytokines with quite divergent functions are now characterized. As human life expectancy has risen in the last decades, due to advances in medicine, the prevalence of chronic, inflammatory, debilitating diseases of infectious or autoimmune origin has risen as well. Recently, inflammatory cytokines have been shown to play a central regulatory role not only in infection and immunity, but also in carcinogenesis, transplantation and other more common chronic conditions such as cardiovascular disease. As soon as a role for these molecules in the pathogenesis of such common diseases was established, novel therapeutic strategies were devised attempting to correct existing inflammatory mediator or cytokine imbalances, by either blocking the effects of certain cytokines or enhancing the presence of others. The first steps toward developing cytokine therapeutics were in the early 1980's. Since then there has been an explosion of interest in this area. The numerous animal and human cytokine based studies in the treatment of such disorders within the last twenty-five years are impossible to cover in a single journal issue. This issue therefore focuses on recent advances in this topic in 6 representative areas of research: chronic infections, allergy, asthma, cancer, transplant medicine and regenerative medicine. In the first article [1], Villar and Dongari-Bagtzoglou present recent information on advances in the use of cytokines as a therapeutic strategy in chronic bacterial, parasitic, fungal and viral infections. In all chronic infections it is generally accepted that for immune protection to take place, generation of a dominant Th1 or Th2 cell type cytokine response is required. In the first part of the article, the role of Th1, Th2 and proinflammatory cytokines as regulators of phagocytic cell function, cell-mediated immunity and humoral immunity, is described. Subsequently, the article discusses the regulation of host protective immunity by specific cytokines in some of the most common chronic infections and addresses potential therapeutic applications of such cytokines in animal models of infection and human trials when data are available. The paper by Woodfolk [2] addresses the role of cytokines in the pathogenesis of allergic disorders, such as asthma. Emerging concepts in the existing Th1/Th2 cytokine paradigm and the identification of a relevant molecular target for therapy are described. This article particularly highlights the challenges of dissecting the role of each cytokine as part of a complex network, in the development of allergic responses to antigens and the manifestation of allergic symptoms. The effects of existing and emerging therapies, which target Th1, Th2 and regulatory cytokines on established allergic responses are discussed. Camateros and coworkers [3] expand the information provided in this issue on allergic diseases by focusing on the role of Toll-like receptor (TLR)-regulated cytokines in the pathogenesis of asthma. In the introductory segment of this article TLR-mediated signaling is linked to specific immunomodulating cytokines, which contribute to the asthmatic phenotype. Specific therapeutic applications of TLR agonists and antagonists in animal models of the disease and future therapeutic prospects are extensively covered. In the fourth paper in this series Mutoh and coworkers [4] address the role of cyclooxygenase-derived mediators of inflammation (prostanoids) in the pathogenesis of cancer. Specific cellular mechanisms of disease pathogenesis, mediated by prostaglandins are addressed such as cell proliferation, modulation of apoptosis, angiogenesis and immune surveillance. Evidence in colon carcinogenesis for the contribution of cyclooxygenases in disease progression is presented. Furthermore, potential applications of prostanoid receptor inhibitors or agonists for cancer chemoprevention are discussed. In the article by De Sanctis et al. [5], cytokines and inflammatory mediators are discussed in the context of allotransplantation and allograft rejection. The specific cytokine-regulated immunologic mechanisms involved in acute and chronic graft rejection, are described.....

The recent increase in immunocompromised patient populations, including HIV-infected patients, cancer patients with chemotherapy-induced neutropenia, and transplant recipients receiving immunosuppressive therapy, has led to an increased incidence of clinically significant chronic opportunistic infections. Traditional treatment of chronic persistent infections has strongly relied on the use of antimicrobial drugs. However, unsatisfactory results with drug monotherapy and emergence of resistant strains have prompted the use of adjunctive cytokine therapies for the treatment of these infections. During the past decade, a wide spectrum of immunomodulators has been tested in human clinical trials and animal models of chronic infections caused by a variety of bacteria, fungi, viruses and parasites. This review compiles recent information on advances in the use of cytokines as a therapeutic strategy in chronic bacterial, parasitic, fungal and viral infections.

Production of IgE antibodies promotes the development of allergic disorders such as asthma, rhinitis and atopic eczema. Though Th2 cytokines play a pivotal role in the allergic inflammatory cascade, therapeutic strategies which target these factors have not been curative in clinical trials. In humans, the allergic phenotype encompasses a broad spectrum of diverse clinical entities, which are dictated by genetics as well as the nature of the allergen and the time in life at which allergen is encountered. The disparate findings in animal and human systems highlight the complexity of cytokinemediated events in allergic responses in man. Different allergic phenotypes cannot be distinguished strictly on the basis of Th1 and Th2 cytokines. These observations coupled with an emerging role for regulatory T cells in modulation of the allergic response warrant re-examination of the cytokine network in allergic disease. This article highlights the challenges of dissecting the role of individual cytokines in the development of allergic responses and manifestation of allergic symptoms. Regulatory T cells have been implicated in modulation of the activity of allergen-specific Th1 and Th2 effector cells and immune outcome; however, the characteristics of these regulatory T cells remain largely undefined. The effects of existing and emerging therapies which target Th1, Th2 and regulatory cytokines on established allergic responses are examined in the context of this new paradigm. Taken together, existing data suggest that a multi-faceted approach, which is tailored to each patient, will be required in order to attain clinical benefit.

Asthma is a complex disease caused by a poorly characterized set of genetic and environmental factors whose pathology is a result of immune dysregulation. Toll-like receptors are pathogen associated molecular pattern receptors expressed by many airway and pulmonary tissues as well as cells of the innate and adaptive immune system. Ligation of toll-like receptors can lead to a change in the expression levels of multiple inflammatory and anti-inflammatory mediators which are involved in the pathogenesis of asthma. These ligands and their receptors are therefore prime candidates in the search for immunotherapeutic treatments of asthma. The use of murine models of allergic asthma as tools for the genetic dissection of this disease should allow the molecular mechanisms underlying asthma to be identified and possibly used as further immunotherapeutic targets.

Prostanoids are produced in response to numerous growth factors and environmental stimuli. Their synthesis is dependent on two cyclooxygenase (COX) enzymes, COX-1 and COX-2, which are rate-limiting for the production of prostaglandins (PGs) and thromboxanes from free arachidonic acid. Selective inhibitors of both COX forms have the potential to inhibit colon tumorigenesis, and there is abundant documented evidence of elevated expression of COX-2 in colon tumors and a variety of other malignancies. The resultant high level PGE2 production may play an important role in cell proliferation, modulation of apoptosis, angiogenesis, inflammation and immune surveillance. Prostanoids exert their biological actions through binding to eight specific membrane receptors; the four subtypes EP1 to EP4 for PGE2; DP for PGD2; FP for PGF2; IP for PGI2; and TP for thromboxane A2. Recently, genetic and pharmacologic experiments have suggested that all PGE2 receptors can contribute to colon tumorigenesis. Moreover, it is suggested that EP1 and EP4 play roles in polyp formation independently. It is important to determine details of the down-stream signaling pathways of prostanoid receptors for further understanding of the mechanisms of cancer development. Furthermore, it is anticipated that development of specific receptor antagonists will provide new advantageous tools for chemoprevention.

Understanding of the mechanisms of transplant and xenotransplant rejection represents one of the most important aspects of both basic and clinical immunology. This review discusses the roles of 1) immune response and 2) the influence of various products of arachidonic acid metabolism on immune response in graft survival. The review also includes an overview of novel therapeutic approaches developed to prevent, or at least delay, graft rejection. New discoveries in basic and clinical immunology have generated new areas of research in pharmacology that may prevent rejection more efficiently, a key issue in modern medicine.

Regeneration that takes place in the human body is limited throughout life. Therefore, when organs are irreparably damaged, they are usually replaced with an artificial device or donor organ. The term "regenerative medicine" covers the restoration or replacement of cells, tissues, and organs. Stem cells play a major role in regenerative medicine by providing the way to repopulate organs damaged by disease. Stem cells have the ability to self renew and to regenerate cells of diverse lineages within the tissue in which they reside. Stem cells could originate from embryos or adult tissues. Growth factors are proteins that may act locally or systemically to affect the growth of cells in several ways. Various cell activities, including division, are influenced by growth factors. Cytokines are a family of low-molecular-weight proteins that are produced by numerous cell types and are responsible for regulating the immune response, inflammation, tissue remodeling and cellular differentiation. Target cells of growth factors and cytokines are mesenchymal, epithelial and endothelial cells. These molecules frequently have overlapping activities and can act in an autocrine or paracrine fashion. A complex network of growth factors and cytokines guides cellular differentiation and regeneration in all organs and tissues. The aim of this paper is to review the role of growth factors and cytokines in different organs or systems and explore their therapeutic application in regenerative medicine. The role of stem cells combined with growth factors and cytokines in the regeneration of vascular and hematopoietic, neural, skeletal, pancreatic, periodontal, and mucosal tissue is reviewed. There is evidence that supports the use of growth factors and cytokines in the treatment of neurological diseases, diabetes, cardiovascular disease, periodontal disease, cancer and its complication, oral mucositis. After solving the ethical issues and establishing clear and reasonable regulations, regenerative medicine through stem cell application combined with specific growth factors and cytokines will have great potential in curing a variety of human diseases.

Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. The reemergence of tuberculosis as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant strains have created a need for the development of new antimycobacterial agents. Mycolic acids, the hallmark of mycobacteria, are high-molecularweight α-alkyl, β-hydroxy fatty acids, which appear mostly as bound esters in the mycobacterial cell wall. The product of the M. tuberculosis inhA structural gene (InhA) has been shown to be the primary target for isoniazid (INH), the most prescribed drug for active TB and prophylaxis. InhA was identified as an NADH-dependent enoyl-ACP reductase specific for long-chain enoyl thioesters. InhA is a member of the mycobacterial Type II fatty acid biosynthesis system, which elongates acyl fatty acid precursors of mycolic acids. Although the history of chemotherapeutic agent development demonstrates the remarkably successful tinkering of a few structural scaffolds, it also emphasizes the ongoing, cyclical need for innovation. The main focus of our contribution is on new data describing the rationale for the design of a pentacyano( isoniazid)ferrateII compound that requires no KatG-activation, its chemical characterization, in vitro activity studies against WT and INH-resistant I21V M. tuberculosis enoyl reductases, the slow-onset inhibition mechanism of WT InhA by the inorganic complex, and molecular modeling of its interaction with WT InhA. This inorganic complex represents a new class of lead compounds to the development of anti-tubercular agents aiming at inhibition of a validated target.

Antithrombotic therapy has improved the prognosis of patients with venous or arterial thrombosis. However, there is substantial interindividual variability in the response to antithrombotic drugs. This variability is due, in part, to genetics, which may affect the efficacy and safety of drugs used in the treatment and prevention of thrombosis. Pharmacogenetics studies the genetic factors related to interindividual variability in the response to drugs. Various polymorphisms in genes of the hemostatic system that have been reported to be markers of susceptibility to thromboembolic disease also seem to be implicated in the response to antithrombotic therapy. These include polymorphisms in platelet receptors (platelet glycoproteins) and coagulation factors (factors II, V, XII, XIII). There is also growing evidence on genetic polymorphisms affecting the metabolism (cytochrome P450), disposition, transporter proteins or cellular receptors of antithrombotic dru This review summarizes current knowledge on the pharmacogenetics of antithrombotic therapy, paying special attention to four therapeutic groups: antiplatelet agents, anticoagulants (vitamin K antagonists and heparin), fibrinolytics and other drugs used for the prevention of cardiovascular risk, such as statins and hormone replacement therapy in the menopause. The potential relevance of pharmacogenetics in the future of antithrombotic therapy and the design of clinical trials is also explored.

Inflammation is a complex pathological condition associated with exaggerated human immune system involving various activated immune cells and bio-molecules. Treatment of inflammatory diseases perticularly chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease etc. has been a big challenge for scientists as there are no safe drugs available for cure. Current therapeutic approaches to the treatment of inflammatory diseases are centered on cycloxygenase (both COX-1 and 2) proinflammatory enzymes but present available drugs of this category are associated with undesirable gastrointestinal and cardiovascular side effects. Recent scientific advents draw out the secrets of inflammation cache and understanding the involvement of several factors acting as stimulators or inhibitors thus opening new avenues for drug discoveries. Several bio-molecules such as proinflammatory cytokines, components of signal trasduction and matrix degrading enzymes resolve inflammatory responses, might be new targets for treatment of chronic inflammatory diseases. This review gathers recent advances in drug research focusing interleukin-1, TNF-α,p38 kinase, c-Jun N-terminal kinase MAP kinase, NFκB, and matrix metalloproteinases. The biological roles of these inflammatory mediators are clearly understood thus offering new targets for design of novel inhibitors for incurable inflammatory diseases. This also provides an overview of the current nonsteroidal antiinflammatory agents.