Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 10, Issue 1, 2010

The treatment against cancer is being flooded by targeted therapies. Imatinib mesylate (Gleevec©) was the first molecule to provide the proof of principle that targeting an aberrant tyrosine kinase responsible for the uncontrolled cell cycle progression allows for the eradication of tumors. The ideal targeted therapy should eliminate the molecular event responsible for the disease, an oncogenic product such as c-KIT, ABL/BCR and PDGFRα in the case of Gleevec©. Two issues related to this conceptual advance are raised in clinical practice. First, these therapies might target additional pathways generating side effects. Secondly, non tumoral cells bearing the molecular target might respond and induce additional biological outcomes. This review will summarize the by-stander immune modulations promoted by the paradigmatic compound Gleevec©, leading to unexpected new therapeutic indications.

The reverse cholesterol transport mediated by high-density lipoprotein (HDL) is an important mechanism for maintaining body cholesterol at normal levels and, hence, the critical anti-atherogenic action of the lipoprotein. Recent studies, however, showed that HDL exerts a variety of anti-inflammatory and anti-atherogenic actions independently of the cholesterol metabolism. On the other hand, statins, inhibitors of HMG-CoA reductase, were initially developed to lower low-density lipoprotein cholesterol in plasma, and they are now recognized to exert a variety of pleiotropic or beneficial actions. Thus, although the mechanisms are different, both endogenous HDL and exogenous statins regulate cholesterol balance in a negative manner and exert a variety of beneficial actions independently of their cholesterol-lowering activity. These results raise the possibility that statins act in part through modulating the plasma levels of HDL and/or its actions. Here, we reviewed the cross-talk mechanism between statins and HDL in anti-inflammatory and anti-atherogenic actions, with a focus on scavenger receptor class B type I, one of main players involved in the cholesterol metabolismindependent HDL actions, and its downstream signaling pathway, leading to the activation of endothelial nitric oxide synthase and the inhibition of adhesion molecule expression in endothelial cells.

The rising incidence of diabetes, metabolic syndrome, and subsequent vascular diseases is now a major public health problem in industrialized countries. New therapeutic strategies to prevent these diseases are urgently needed worldwide. It is well known that calorie restriction (CR) can retard the aging process in organisms ranging from yeast to rodents, and delay the onset of numerous age-related diseases including diabetes. Molecules that mimic CR metabolically are therefore potentially new therapeutic targets for age-related diseases. Silent information regulator 2 (Sir2) is an important player in CR-mediated life span extension. There is also increasing evidence that one of the seven mammalian sirtuins, SIRT1, is involved in regulating cellular processes such as apoptosis. SIRT1 has also been implicated in glucose homeostasis and lipid metabolism in various tissues including adipose tissues, liver, pancreas, and skeletal muscle. This review summarizes current understanding of the biological functions of SIRT1, and discusses its potential as a pharmacological target for fighting metabolic and vascular diseases.

Animal models have enriched understanding of the physiological basis of metabolic disorders and advanced identification of genetic risk factors underlying the metabolic syndrome (MetS). Murine models are especially appropriate for this type of research, and are an excellent resource not only for identifying candidate genomic regions, but also for illuminating the possible molecular mechanisms or pathways affected in individual components of MetS. In this review, we briefly discuss findings from mouse models of metabolic disorders, particularly in light of issues raised by the recent flood of human genome-wide association studies (GWAS) results. We describe how mouse models are revealing that genotype interacts with environment in important ways, indicating that the underlying genetics of MetS is highly context dependant. Further we show that epistasis, imprinting and maternal effects each contribute to the genetic architecture underlying variation in metabolic traits, and mouse models provide an opportunity to dissect these aspects of the genetic architecture that are difficult if not impossible to ascertain in humans. Finally we discuss how knowledge gained from mouse models can be used in conjunction with comparative genomic methods and bioinformatic resources to inform human MetS research.

The worldwide incidence of malignant melanoma has been steadily increasing, and it has become a major public health problem in many countries. Melanoma has been considered as a prototypical “immunogenic” tumor on the basis of clinical observations showing that primary lesions can spontaneously regress and that immunosuppressed individuals have an increased incidence of melanoma. Thus, various immunological therapies have been intensively conducted for the treatment of melanoma. Interleukin(IL)-27 is a IL-12-related heterodimeric cytokine composed of p28 and EBV-induced gene 3 subunits that are structurally related to the p35 and p40 subunits of IL-12, respectively. Recent studies reveal that IL-27 exhibits not only potent antitumor immune activities via cytotoxic T lymphocytes or natural killer cells but also an antiangiogenic effect. We recently clarified that IL-27 possesses an antiproliferative activity on melanoma cells. This review summarizes antitumor responses induced by IL-27 and novel anti-melanoma activities of IL-27.

Thyroid nodules are quite common and present approximately in 10% of the population. Fine-needle aspiration biopsy has become the mainstay of thyroid nodule evaluation and the overall accuracy is excellent; however, some aspirates demonstrating indeterminate cytology results do not permit definitive diagnosis of malignancy, and in addition, there are no clear guidelines for the management of these lesions because the incidence of malignancy in indeterminate aspirates varies in the different studies published. In order to find molecular markers in an attempt to predict malignancy based on cytology, at least 70 molecular or cellular and genetic markers have been studied in thyroid nodules. This review focuses on some potential markers such as thyroid peroxidase, thyroglobulin, telomerase, galectin-3, RET/PTC and protein p53; some of them, such as thyroid peroxidases, thyroglobulin and galectin-3, can be studied in a routine pathology laboratory and are promising, but do not yet fulfil criteria required for their use in clinical practice. The American guidelines and the European consensus for the management of thyroid nodules and differentiated thyroid cancer do not recommend their systematic use because the evidence that they have provided is insufficient. On the other hand, information obtained through cytological smears permits the study of complex metabolic or genetic pathways, providing researchers with a high throughput tool to elucidate changes in the global expression patterns seen in tumour cells. This ability to take tumour biology into account would allow the selection of different drugs, considering the predominant altered pathways observed in these samples. Finally, all these data may provide the molecular groundwork for permitting future preoperative discrimination of follicular adenomas from hyperplastic nodules, and may ultimately guide therapeutic strategies.

Epidemiological studies indicated that more than 15% of the population in western countries suffer because of severe forms of periodontitis. In this respect, the recognition of the relationship between oral and systemic health is growing, thus receiving remarkable interest in scientific literature. In fact, periodontitis may increase the risk for a group of life-threatening conditions such as atherosclerosis, stroke or low birth weight. The American Diabetes Association has reported that individuals with uncontrolled diabetes (defined as 200mg/dL of glucose on three consecutive readings) undergo an increased risk of infections, abnormal wound healing and consequent increased recovery time. Moreover, diabetics may be more likely to develop periodontal and cardiovascular disease than non diabetics, if note. History of poorly controlled chronic periodontal disease can alter diabetic/glycemic control. This may originate from a likely continuous passage of bacterial toxins and/or bacteria into the bloodstream, and/or from an exaggerated release of inflammatory mediators. This review is aimed at elucidating the connections between the status of oral health and glycemic control in diabetes.

Bovine African trypanosomiasis causes severe economical problems on the African continent and one of the most prominent immunopathological parameters associated with this parasitic infection is anemia. In this report we review the current knowledge of the mechanisms underlying trypanosomiasis-associated anemia. In first instance, the central role of macrophages and particularly their activation state in determining the outcome of the disease (i.e. trypanosusceptibility versus trypanotolerance) will be discussed. In essence, while persistence of classically activated macrophages (M1) contributes to anemia development, switching towards alternatively activated macrophages (M2) alleviates pathology including anemia. Secondly, while parasite-derived glycolipids such as the glycosylphosphatidylinositol (GPI) induce M1, host-derived IL-10 blocks M1-mediated inflammation, promotes M2 development and prevents anemia development. In this context, strategies aimed at inducing the M1 to M2 switch, such as GPI-based treatment, adenoviral delivery of IL-10 and induction of IL-10 producing regulatory T cells will be discussed. Finally, the crucial role of iron-homeostasis in trypanosomiasis-associated anemia development will be documented to stress the analogy with anemia of chronic disease (ACD), hereby providing new insight that might contribute to the treatment of ACD.

It has come to our notice that the article published in Current Drug Targets-Immune Endocrine and Metabolic Disorders, Volume 4, Issue 1, page numbers 75-78, is largely the same as that published in the Journal Biochemical Pharmacology. The publishers have therefore decided to retract the article in question.