Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 9, Issue 3, 2009

Peroxisome proliferator-activated receptor alpha (PPAR??) regulates transcription of genes involved both in lipid and glucose metabolism as well as in inflammation. Fibrates are PPARα ligands used to normalize lipid and glucose parameters and exert antiinflammatory effects. In fact, fibrates have already been demonstrated to benefit metabolic syndrome, type 2 diabetes and cardiovascular diseases. This article reviews the mechanism of action and the functional roles of fibrates, emphasizing the factors modulating their capacity to activate PPARα and affecting their effectiveness. These factors may possibly explain the findings obtained in animal studies and clinical trials with fibrates which showed either untoward effects and/or inefficient hypolipidemic action of PPARα activation. We also discuss briefly the natural and synthetic agonists of PPARαwhich are currently being developed and supposedly display greater effectiveness and fewer adverse effects than fibrates.

The statins are a group of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase that are used extensively in medical practice because of their ability to reduce cardiovascular mortality and stroke. Although this protective activity was initially ascribed to the inhibition of cholesterol biosynthesis in the liver, clinical trials and basic research studies indicate that, beyond their cholesterol-lowering activity, statins might affect the function of different cell types in extrahepatic tissues. Here we will review the different mechanisms by which the statins exert their immunomodulatory and anti-inflammatory functions. We propose that statin pleiotropism is a key to the explanation of these activities, as it enables statins to act cooperatively in various steps of the inflammatory reaction, including terminal differentiation of immune cells, endothelial cell function, and regulation of the molecules that steer these cells to the sites at which they exert their immunomodulatory activity.

Random mutations of the first nucleotide of a coding triplet alter the hydropathic character of 27 % of the hydrophobic amino acids and of 23 % of the hydrophilic amino acids, while random mutations of the second nucleotide alter the hydropathic character of 82 % of the hydrophobic amino acids and of 47 % of the hydrophilic amino acids. In cases of a change of the hydropathic character, a second random mutation in the previously unmutated first or second nucleotide causes reversion to the original character of an additional 11 % of the originally hydrophobic-coding triplets and an additional 14 % of the originally hydrophilic-coding triplets (on average). Thus, a selection oriented towards the preservation of the hydropathic character of amino acids may be expected to eventually result in a higher conservation of the second nucleotide (as compared to the first). In the case of uncorrected mutations of one of the two first nucleotides, it may be expected that appropriate second mutations in the other unaffected nucleotide will be positively selected. This would result in a positive correlation between the conservation/mutation indexes of the two first nucleotides, as these would be prevailingly either both conserved or both mutated. We examined six groups of coding mRNA sequences: chemokine CXC 1 and 4 and formyl peptide receptors; a group comprising different receptors of the rhodopsin-like superfamily, together with some viral sequences which share significant homologies with these receptors; a group of viral sequences with homologies with the rhodopsin-like receptors; a group of solute carriers. In all the experimental groups the second nucleotide of the triplet was the most conserved and a significant positive correlation existed between conservation/mutation indexes of the two first nucleotides. Similar conservation/mutation patterns could be of more general occurrence in the genome, as a consequence of selection processes.

Differentiated thyroid cancers are the predominant malignancies of the thyroid. Due to advances in the understanding of the activation of the cell proliferation pathway at a molecular level, multiple genetic alterations have been linked to the development of thyroid carcinogenesis. Although the genetic alterations can be categorized into 7 categories, the BRAF mutation, RET/PTC, Pax8/PPARGamma, and dysfunctional Fas pathway have been most commonly described. Each of the gene alterations can ultimately result in cancer development, invasion and/or metastasis. This article provides a detailed review of the altered cell proliferation pathway activations found in thyroid carcinogenesis. The molecular targets that may be disrupted by therapeutic agents during the abnormal proliferation are also summarized.

Endocrine system is one of the most sensitive communication networks of the human body, which influences all aspects of human health and well-being, including reproductive potential, cognitive functions, thyroid and metabolism, digestion and hormonal balance. In recent years, basic laboratory research has been focused on the potential relationship between environmental contaminants and cellular endocrine function. Environmental contaminants are ubiquitous in the environment, alter endocrine physiology and produce endocrine disruption without acting as classic toxicants. These endocrine disruptors (EDCs) are lipophilic and stored for long period of time in the adipose tissue. Maternal exposure to EDCs during pregnancy and lactation has resulted in the exposure of the fetus and neonate through placenta and breast milk. It has been recognized that human milk is the best natural food for neonates providing immunologic, developmental and practical advantages throughout the childhood. However, contamination of human milk by the presence of environmental toxicants is widespread through the past decades due to inadequately controlled pollution. Persistent pesticides, chemical solvents and others tend to slowly invade the environment, bioaccumulate in the food chain, and have long halflives in animals and humans. During the past fifteen years, the scientific interest has been focused on xenoestrogens, i.e., environmental chemicals with estrogen disrupting activity. Certain adverse health and reproductive outcomes are attributed to these chemicals in wildlife, in laboratory animals, as well as in humans. Although most toxic agents are hazardous in high doses, the human health risks are associated with EDCs concern exposure to low doses. The human health risks that may be associated with these low-level but constant exposures, are still largely unknown and highly controversial. In this paper, we review available data on environmental chemicals present in breast milk that may affect child health through breastfeeding. Specifically, we focused on the breast-feeding pharmacokinetic aspects related to infant exposure of chemical pollutants that have estrogen and antiandrogen activities, such as environmental estrogen disruptors or xenoestrogens.

Micronutrients, mostly iodine and selenium, are required for thyroid hormone synthesis and function. Iodine is an essential component of thyroid hormones and its deficiency is considered as the most common cause of preventable brain damage in the world. Nowadays about 800 million people are affected by iodine deficiency disorders that include goiter, hypothyroidism, mental retardation, and a wide spectrum of other growth and developmental abnormalities. Iodine supplementation, under form of iodized salt and iodized vegetable oil, produced dramatic improvements in many areas, even though iodine deficiency is still a problem not only for developing countries. In fact, certain subpopulations like vegetarians may not reach an adequate iodine intake even in countries considered iodine-sufficient. A reduction in dietary iodine content could also be related to increased adherence to dietary recommendations to reduce salt intake for preventing hypertension. Furthermore, iodine intakes are declining in many countries where, after endemic goiter eradication, the lack of monitoring of iodine nutrition can lead to a reappearance of goiter and other iodine deficiency disorders. Three different selenium-dependent iodothyronine deiodinases (types I, II, and III) can both activate and inactivate thyroid hormones, making selenium an essential micronutrient for normal development, growth, and metabolism. Furthermore, selenium is found as selenocysteine in the catalytic center of enzymes protecting the thyroid from free radicals damage. In this way, selenium deficiency can exacerbate the effects of iodine deficiency and the same is true for vitamin A or iron deficiency. Substances introduced with food, such as thiocyanate and isoflavones or certain herbal preparations, can interfere with micronutrients and influence thyroid function. Aim of this paper is to review the role of micronutrients in thyroid function and diseases.

With the development of biologicals that specifically target tumor necrosis factor (TNF)α, our therapeutic approach to inflammatory diseases has dramatically changed. There are currently three anti-TNFα drugs available: etanercept, infliximab, and adalimumab. Etanercept is a recombinant fusion protein that can be used alone or in combination with other medications for conditions such as rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, psoriasis, and ankylosing spondylitis. Infliximab, a chimeric humanized monoclonal antibody and adalimumab, a fully human monoclonal antibody are approved for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and moderate to severe Crohn's disease. Infliximab is also approved for ulcerative colitis, adalimumab for juvenile rheumatoid arthritis. Another anti-TNFα drug, certolizumab pegol, was declined EMEA approval as treatment option for active Crohn's disease . However, in the USA it was approved by the FDA to treat moderate to severely active Crohn's disease in adults who have not been helped by usual treatments (April 2008) in addition to the treatment of moderately to severely active rheumatoid arthritis (May 2009). It is the goal of this review article to summarize various therapeutic indications, underlying studies, safety, and use during pregnancy, as well as future directions for anti-TNF therapies.