Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 7, Issue 4, 2007

Tetracycline and its derivatives, such as chlortetracycline, oxytetracycline, minocycline, doxycycline, methacycline and lymecycline, are naturally occurring or semi-synthetic polyketide compounds that exhibit a well known broadspectrum antibacterial activity that interferes with prokaryotic protein synthesis at the ribosome level. In addition to this well known antibacterial activity these compounds also exhibit a variety of additional, less well known properties. Among them are separate and distinct anti-inflammatory properties. Tetracycline and related compounds have been shown to be effective chemotherapeutic agents in a wide variety of chronic inflammatory diseases and conditions. These include periodontitis, rosacea, acne, auto-immune diseases such as rheumatoid arthritis and protection of the central nervous system against trauma and neurodegenerative diseases such as stroke, multiple sclerosis and Parkinson disease. Tetracycline and related compounds appear to be beneficial for treatment of several chronic inflammatory airway diseases. Among them are asthma, bronchiectasis, acute respiratory distress syndrome, chemical induced lung damage and cystic fibrosis. The clinical use of tetracycline-type drugs in treatment of chronic airway inflammation is becoming a topic of intense interest. Recent findings in this area have led to an understanding of the myriad physiological, cellular and molecular mechanisms of the inflammatory response and how this response may be controlled to limit damage to host cells and tissues. This review presents a brief summary of the recent research in the area of tetracycline and its derivatives in control of pulmonary inflammation.

The introduction of highly active antiretroviral therapy (HAART) including nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI) has dramatically improved the morbidity and mortality in HIV-infected patients. Unfortunately, HAART has been associated with several side effects among which the development of lipodystrophy syndrome remains a major clinical issue. It is characterized by fat redistribution dominated by peripheral fat loss and complex metabolic alterations including dyslipidemia and insulin resistance. Dissection of the pathogenesis of the lipodystrophy syndrome is hampered by several factors: all HIV-patients receiving HAART have a chronic and often advanced illness with impact on metabolism and energy homeostasis. Secondly, almost all patients are receiving various combinations of drugs that simultaneously reduce viral replication and restore the immune system. Recently, more detailed clinical studies, experiments using animal models and in vitro systems have been successfully used to elucidate important pathogenic aspects. At the same time, partial reversion of fat loss and metabolic disturbances in HIV-patients could be achieved by omitting components of HAART or administration of metabolically active drugs. Here, we will summarize the current knowledge about the molecular alterations that are induced by antiretroviral therapy and possibly contribute to the lipodystrophy syndrome. Specific attention will be given to the role of NRTI and PI on adipocyte development, function, and mitochondrial integrity leading to fat loss, fat accumulation, and increase of serum lipids.

The recent technological advances in high-throughput gene expression analysis allow the simultaneous investigation of thousands of genes. These technologies represent promising tools for the identification of new drug targets and considerable progress has been achieved in cancer research where microarray data provide a basis to design new drugs and to predict adverse reactions and the efficacy of chemotherapy. The metabolic syndrome represents a cluster of disorders including high blood pressure, insulin resistance/type 2 diabetes mellitus, visceral obesity and dyslipidaemia with fatty liver disease being a common associated complication. Highthroughput gene expression analyses using GeneChips, microarrays and serial analysis of gene expression (SAGE) have been applied to study global gene expression in insulin resistance/type 2 diabetes mellitus. Type 2 diabetes mellitus is a multifactorial and polygenic disease by which several organs are affected. Therefore, the identification of both, disease causing and therapeutically relevant target genes is an ambitious challenge. In the present review we focus on genomic approaches that used biopsies from human skeletal muscle, liver and adipose tissue, the main organs affected by insulin resistance. Members of the PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators are decreased in skeletal muscle in insulin resistance accounting for the reduced expression of genes involved in mitochondrial oxidative phosphorylation. Hepatic steatosis is also linked to alterations in mitochondrial phosphorylation and oxidative metabolism. An up regulation of pro-inflammatory genes can be detected in early stages of fatty liver disease without histological signs of inflammation. Impaired adipogenesis, intra-adipose accumulation of macrophages and a sustained release of inflammatory and acute phase proteins are characteristic features of adipose tissue in obesity and may aggravate systemic insulin resistance.

The review surveys potential “structural antigens” which represent small protein domains that can be chemically synthesized and, isolated from the context of the whole protein, can fold in the same native structure. They include natively unfolded protein regions, small globular domains, α-helical coiled coils and regions with tandem repeats forming structures ranging from the collagen triple helices to solenoid-like arrangements. We also describe and compare new strategies for development of vaccine that use the concept of structural epitopes. One type of approach is based on engineering artificial mini-proteins able to mimic structural epitopes of natural proteins. The review compares the “engineering” methodologies with “bioinformatics” approaches that became possible recently, after the sequencing of the genomes of many pathogens, and involve genome-wide bioinformatics searches for “structural antigens”. In particular, based on the known P. falciparum genome, we identified putative α-helical coiled coil regions, 30-40 amino acids long, in proteins presented in asexual malaria blood stages. Peptides of such regions frequently fold into the “native” structure. A hundred such peptides were synthesized and all of them were recognized at various degrees (5-80%) by a panel of sera from donors living in malaria-endemic areas. The results obtained demonstrate that a bioinformatics/chemical synthesis strategy can rapidly lead to the identification of new proteins that can be targets of potential vaccines and/or drugs against malaria and other infectious organisms.

Cytokine therapy can induce tumor regression in cancer patients but systemic administration of cytokines is accompanied with severe toxicity. Loco-regional delivery represents an effective and less toxic alternative to systemic injection. However; the requirement for frequent repeated injections of recombinant cytokine or the logistical difficulties associated with gene-modification have limited wide-spread use of loco-regional therapy. A simpler alternative local delivery strategy involves the use of controlled-release cytokine depot formulations. These formulations provide the advantage that physiological doses of cytokines are directly released to the tumor microenvironment in a sustained manner. Anti-tumor efficacy of IL-2; IL-12; GM-CSF or TNFα-encapsulated polymer microspheres has been evaluated in syngeneic murine and human tumor /SCID mouse xenograft models. A single intra-tumoral injection of these formulations; particularly that of IL-12 in combination with GM-CSF or TNFα; promoted the regression of established primary tumors; induced systemic anti-tumor T- and NK-cell responses and achieved complete eradication of disseminated disease. Cellular and molecular analysis of post-therapy tumor microenvironment demonstrated that treatment promoted the activation of tumorassociated T-effector/memory cells; the elimination of CD4+ CD25+ Foxp3+ T-suppressors and the de novo priming of tumor-specific CD8+ T-effector cells. Long-term monitoring of post-therapy tumors revealed that reversal of intratumoral immune suppression was transient and that T-suppressor cells rapidly re-infiltrated tumors. Repeated treatment resurrected anti-tumor activity; however, therapeutic efficacy declined with each treatment cycle. The observed loss of therapeutic efficacy was associated with a progressive intensification of the post-treatment T-suppressor cell rebound. In contrast; depletion of T-suppressor cells with low dose chemotherapy prior to each cycle of treatment resulted in a dramatic enhancement of long-term therapeutic efficacy leading to complete remissions. Clinical implications of these findings are discussed herein.

Modern molecular nutrition focuses on health promotion, disease prevention and performance improvement through diet. In analogy to Pharmacogenetics and -genomics, the disciplines “Nutrigenetics” and “Nutrigenomics” have evolved. Nutrigenetics asks how individual genetic disposition, manifesting as single-nucleotide- and copy-number polymorphisms as well as epigenetic regulation, affects susceptibility to diet. Nutrigenomics addresses the inverse relationship, i.e. how diet influences gene transcription, protein expression and metabolism. The long-term objective of Nutrigenomics is personalised nutrition for maintenance and improvement of individual health and for disease prevention. Transcriptomics can put Proteomics- and Metabonomics-derived markers into a larger biological perspective. Metabonomics is a diagnostic tool for metabolic classification of individuals with the asset of quantitative, non-invasive analysis of easily accessible human body fluids such as urine, blood and saliva. This feature also applies to some extent to Proteomics, with the constraint that the latter discipline is more complex in terms of composition and dynamic range of the sample. Apart from addressing the most complex “Ome”, Proteomics represents the only platform that delivers not only markers for disposition and efficacy but also targets of intervention. Application of integrated Omic technologies will drive the understanding of interrelated pathways in healthy and pathological conditions and will help to define molecular ‘switchboards’, necessary to develop disease related biomarkers. This will contribute to the development of new preventive and therapeutic strategies for both pharmacological and nutritional interventions. This paper reviews inflammatory gut disorders, the state-of-the-art of the three Omics platforms and discusses the implication of the latter in biomarker revelation for nutritionally actionable inflammatory disorders in the intestine.

In both Crohn's disease (CD) and ulcerative colitis (UC), the major forms of inflammatory bowel diseases (IBD) in humans, the pathologic process consists of an aberrant local immune response to components of the bacterial microflora, due to abnormally strong effector cell activity that is poorly controlled by counter-regulatory mechanisms. There is also evidence that mucosal immune cells actively interact with non-immune cells to promote tissue damage, and that cytokines are essential mediators of this cross-talk. Interleukin-21 (IL-21), the latest member of the common γ-chain-dependent cytokine family, is a product of activated CD4+ T cells and natural killer T cells. IL-21 is produced in excess in CD tissue, where it helps sustain the ongoing Th1 inflammation. High IL-21 production occurs also in the inflamed colon of most patients with UC, a disease that is not associated with a marked Th1 cell response. This suggests that, in the gut, IL-21 can modulate additional inflammatory pathways other than enhancing Th1 cell immunity. Indeed, IL-21 stimulates the secretion of extracellular matrix degrading enzymes by fibroblasts, and of the T cell chemoattractant, MIP-3α, by epithelial cells. These data collectively indicate that IL-21 is a mediator of the chronic inflammatory response in CD and UC, and suggest that IL-21 may be an emerging therapeutic target in IBD.

Multiple Sclerosis is an inflammatory and degenerative disorder involving the central nervous system. It primarily affects young adults and may result in significant long-term disability. The most common initial presentation is relapsing remitting, followed by a chronic progressive course. In a small number of patients the disease tends to be progressive from onset. Multiple sclerosis has traditionally been described as a demylinating disorder. There is now overwhelming evidence pointing to a very significant degenerative component. Current treatment options include immunomodulating and immunosuppressive agents as well as monoclonal antibodies and target the inflammatory component of the disease resulting in significant reduction in relapses, decrease in MRI lesion load and a modest effect on disability. There are several other biological agents being developed which target different aspects of the immunopathology of multiple sclerosis. This article will review the agents currently used in the treatment of MS and also discuss agents currently under development.

Epidemiological and experimental data supporting a role for luteinizing hormone in Alzheimer disease is accumulating. Paralleling the female predominance for developing Alzheimer disease, luteinizing hormone levels are significantly higher in females as compared to males and luteinizing hormone levels are higher still in individuals who succumb to Alzheimer disease. Importantly, luteinizing hormone, which is capable of modulating cognitive behavior, is not only present in the brain, but also has the highest receptor levels in the hippocampus, a key processor of cognition that is severely deteriorated in Alzheimer disease. These findings, together with data indicating that luteinizing hormone modulates amyloid-β protein precursor processing in vivo and in vitro, suggests that luteinizing hormone may contribute to Alzheimer disease pathology through an amyloid-dependent mechanism. Indeed, abolishing luteinizing hormone, using a potent gonadotropin-lowering agent, leuprolide acetate, in the amyloid-β protein precursor transgenic mice improved hippocampally- related cognitive performance and decreased amyloid-β deposition. These promising findings support the importance of luteinizing hormone in Alzheimer disease and bring to the forefront an alternative, and much needed therapeutic avenue for the treatment of this insidious disease.

The metabolic state affects the level of general activity of an organism. Satiety is related to relaxation while hunger is coupled to elevated activity which supports the chance to balance the energy deficiency. The unrestricted food availability in modern industrial nations along with no required locomotor activity are risk factors to develop disorders such as obesity. One of the strategies to find new targets for future treatment of metabolic disorders in men is to gain detailed knowledge of molecular and cellular mechanisms involved in the regulation of metabolic homeostasis in less complex, i.e. invertebrate systems. This review reports recent molecular studies in insects about how hunger signals may be linked to global activation. Adipokinetic peptide hormones (AKHs) are the insect counterpart to the mammalian glucagon. They are released upon lack of energy and mobilize internal fuel reserves. In addition, AKHs stimulate the locomotor activity which involves their activity within the central nervous system. In the cockroach Periplaneta americana various neurons express the AKH receptor. Some of these, the dorsal unpaired median (DUM) neurons belonging to a general arousal system, release the biogenic amine octopamine, the insect counterpart to mammalian adrenergic hormones. The two Periplaneta AKHs activate Gs proteins, and AKH I also potently activates Gq proteins. AKH I and - less effectively - AKH II accelerate spiking of DUM neurons via an increase of a pacemaking Ca2+ current. Systemically injected AKH I stimulates locomotion in contrast to AKH II. This behavioral difference corresponds to the different effectiveness of the AKHs on the level of G-proteins.