Current Drug Targets - Immune, Endocrine & Metabolic Disorders - Volume 5, Issue 3, 2005

All major advances in the development of hormonal methods of contraception over the past 40 years have been exclusively female orientated with male hormonal contraception forever "just around the corner". Despite this, the last few years have seen a significant increase in the pace of research and increased involvement from the pharmaceutical industry. This is essential if the progress derived from the public sector is to be translated into a real product for widespread use. Current male methods of contraception, condoms and vasectomy, are relied on by 30% of couples throughout the world but there have been no new male contraceptive methods introduced in the last century. There is currently an increasing emphasis on male involvement in family planning, and evidence both that some men would be keen to shoulder this responsibility and that their partners would trust them to do so. There are several potential novel approaches to male contraception, but the hormonal one is the only one at the stage of clinical research. This method is based on the normal regulation of spermatogenesis by the pituitary gonadotrophins: suppression of gonadotrophin secretion results in a reduction in the rate of spermatogenesis, and azoospermia, the absence of sperm from the ejaculate, can be achieved. Current approaches are now getting close to the ideal of inducing azoospermia in all men. This approach also results in suppression of testicular testosterone production, thus androgen 'add-back' is an essential component of a contraceptive regime. Many different steroids and delivery methods -oral, buccal, transdermal, subcutaneous implants- are under exploration at present, each with their own advantages and drawbacks. The use of synthetic androgens is also starting to be explored: these have the potential advantage of offering tissue-specific actions.

Pituitary adenomas are neuroendocrine tumors that produce different endocrine and metabolic alterations, including hyperprolactinemia, acromegaly and Cushing's disease. These different clinical features of pituitary tumors are the result of the overproduction of hormones produced by the different pituitary cell types. Recent advances in the understanding of the signaling pathways that control hormone production in pituitary cells provide a source of potential therapeutic targets. In ACTH-secreting cells, the mechanisms that control hormone biosynthesis have been clarified to a great extent, indicating a number of protein kinases and ligand-activated nuclear receptors as targets for experimental drugs. ACTH production requires the activation of signal transduction through the PKA, the MAPK and the CamK pathways. These pathways activate nuclear receptors, including Nur and PPAR gamma. The inhibition of these kinases and nuclear receptors has been shown to produce therapeutic effects in mouse models of Cushing's syndrome. On the other hand, the signaling pathways that control prolactin and growth hormone production also have potential targets. It has been recently shown that SMAD proteins activated by growth factors of the TGF beta and BMP family interact with estrogen receptors to stimulate the proliferation of prolactin and growth hormone-secreting cells. Cytokines that bind to the membrane protein gp130 also stimulate the proliferation of these cells. The inhibition of both of these pathways results in the decrease of tumor growth in animal models of prolactinoma. Therefore, the study of signaling pathways that control hormone production and proliferation is a good source of candidate targets in pituitary tumors.

Caspases are intracellular cysteine proteases that mediate cell death and inflammation. Caspase-3 is a major mediator of both apoptotic and necrotic cell death. Caspase-1 mediates inflammation though the activation of the cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). Increases in both caspase-1 and -3 have been described in ischemic injury to various organs including brain, heart and kidney. Both pharmacological inhibitors and genetic approaches have been used to inhibit caspases in vivo. Pancaspase inhibitors protect against ischemic injury in brain, heart and kidney. Pancaspase inhibition also reduces cold preservation injury due to apoptosis in liver endothelial cells and prolongs animal survival after orthotopic liver transplantation. Caspase-1 inhibition or caspase-1 deficiency protects against ischemic injury in brain, heart and kidney models of ischemia. Specifically, impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. This review focuses on studies of caspase-1 and pancaspase inhibition in ischemic injury to brain, heart and kidney. In addition, the studies of pancaspase inhibition in cold ischemic injury and organ preservation will be reviewed. The therapeutic potential of caspase inhibition in ischemic injury will be discussed.

Recent studies reveal that bile acids are signalling molecules that activate several nuclear receptors and regulate many physiological pathways and processes to maintain bile acid and cholesterol homeostasis. Analysis of orphan receptor expression patterns in enterohepatic tissues identified bile acids as ligands for farnesoid X receptor (FXR). The primary bile acid chenodeoxycholic acid (CDCA) was shown to be the most potent FXR ligand in vitro at an EC50 of 10-50 μM. FXR can also be activated by the secondary bile acids lithocholic acid (LCA) and deoxycholic acid (DCA). Upon activation FXR heterodimerises with 9-cis retinoic X receptor (RXR) and regulates a cohort of genes involved in cholesterol catabolism and bile acids biosynthesis. Thus bile acid-activated FXR directly induces expression of Small Heterodimer Partner (SHP), a nuclear receptor that suppresses bile acid biosynthesis down-regulates the Na+ taurocholate cotransport peptide (NTCP), a pump depicted to transport bile acids from the lumen into hepatocyte, and induces expression of bile salt export pump (BSEP), the principal bile acid efflux transporter in the liver. As demonstrated by the Fxr null mice, FXR defends the liver against cholestasis. The 6-ethyl derivative of CDCA (6-ECDCA) is ≈100 fold more potent than CDCA in activating FXR in vitro. In vivo administration of 6-ECDCA protects against cholestasis induced by estrogen and LCA in rats providing evidence that development of potent FXR agonists might represent a new approach for the treatment of cholestastic disorders.

Estrogen receptors (ERα and ERβ) mediate the effects of 17β-estradiol (E2) and account for E2 role on growth, development, and homeostasis maintenance in different tissues and organs. ERα and ERβ function as ligand-dependent transcription factors which directly bind to specific estrogen responsive element (ERE) present into DNA and, in turn, regulate the transcription of E2-sensitive genes. In addition, ERα and ERβ, without direct binding to DNA, regulate transcription indirectly by binding to other transcription factors activating or inactivating the transcription of E2- dependent-ERE-devoid genes. Along with these two E2 mechanisms, it has been recently uncovered that a third signalling pathway, involving cytoplasmic proteins and rapid membrane-initiated responses, serves largely for mitogenic E2-induced effects. The commitment of ERβ in these rapid E2-induced effects is openly debated. This review will focus and summarize the latest findings regarding the multiple E2 molecular mechanisms and underlines the development of our understanding of anti-cancer drugs acting as ER signalling modulators.

NKT cells emerge as important regulatory cells in autoimmune responses. Abnormalities in the numbers and functions of natural killer T (NKT) cells have been observed in patients with autoimmune diseases as well as in a variety of mouse strains that are genetically predisposed for development of autoimmune diseases. Unlike conventional T cells that recognize peptides in association with major histocompatibility complex (MHC), NKT cells recognize glycolipid antigens presented by the non-polymorphic MHC class I-like protein, CD1d. Recently, we and other groups have demonstrated that administration of glycolipid ligands such as a-galactosylceramide (α-GC ) or its sphingosine truncated derivative, OCH suppressed autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), diabetes in NOD mice and collagen-induced arthritis (CIA) by inducing T helper (Th) 2 bias of autoimmune T cells. OCH is a unique ligand to stimulate NKT cells to selectively produce Th2 cytokines whereas α-GC induces both interleukin (IL)-4 and interferon (IFN)-γ, and is more beneficial for treatment of a wide variety of Th1-mediated autoimmune diseases. The lack of polymorphism of CD1d and cross-reactive responses of mouse and human NKT cells to the same ligand indicates that targeting NKT cells with this ligand may be an attractive means for intervening in human autoimmune diseases such as type I diabetes (T1D), multiple sclerosis (MS) and rheumatoid arthritis (RA). The present review will focus on the potential roles of NKT cells in the pathogenesis of autoimmune diseases and the recent advances in glycolipid therapy for autoimmune disease models. The molecular mechanism of OCH-induced Th2- selective cytokine secretion will also be discussed.

Oxidative tissue damage in vivo is a complex phenomenon involving many factors and pathways. Proteins are particularly attractive targets for oxidative products analysis in order to understand better the physiopathology of human diseases. Protein modifications serve as footprints of biochemical processes. They also help ascertain the mechanism of anti-oxidative action of medical drugs and further search for novel agents that inhibit efficiently oxidative protein damage. Several drugs already used clinically interfere with oxidative protein damage through different mechanisms characteristic of their chemical structure. This review delineates the oxidative protein modifications existing in diabetic nephropathy and their regression in association with renoprotective anti-hypertensive agents. Our hypothetical approach will require further testing. Nevertheless, the insights gained on the biochemistry of protein modifications open new avenues towards the development of new classes of renoprotective agents for diabetic nephropathy.

The term "functional food" refers to foods or ingredients of foods providing an additional physiological benefit beyond their basic nutritional needs. Health benefits are best obtained through a varied diet containing fruits, vegetables, grains, legumes and seeds. However, fortified foods and dietary supplements have been marketed and food industry have made functional food one of their current leading trends. Recently, the number of functional foods that have a potential benefit on health has hugely grown and scientific evidence is supporting the role of functional foods in prevention and treatment of several diseases. Cancer, diabetes, heart disease and hypertension are the most important diseases that can be treated or prevented by functional foods; other diseases are osteoporosis, abnormal bowel motility, and arthritis. It has been estimated that 80% of cancer in USA have a nutrition/diet component suggesting a great impact of functional food and foods components on incidence and treatment of cancer. Numerous factors complicate the evaluation of scientific evidence such as the complexity of food substance, effect on food, metabolic changes associated to dietary changes, the lack of biological markers of disease development. This paper reviews the scientific evidence supporting this area regarding only those foods and ingredients in which a clear experimental and clinical evidence exists for their chemopreventive and therapeutic effects.

The increasing outpatient use of colonoscopy in the diagnostic study and prophylaxis of colon diseases has allowed early identification of polypoid neoformations, thus indicating their increased incidence during the asymptomatic phase. In this respect, the application of biological sealants immediately before the polypectomy has represented a novel therapeutic strategy in the treatment of these preneoplastic lesions. The injection of biological sealants with needle under the polyp peduncle or sub-mucosa has demonstrated a protective action on the electrocoagulated area, an antihaemorrhagic effect owing to the strengthened seal of the eschar that is formed, and a facilitated tissue regeneration, respectively. The author report his experience acquired over the past five years with regard to the use of biological sealant in colonoscopic polypectomy and conclude that biological sealants, a human fibrin glue, which utilises components of the human plasma, may allow a more generous removal of neoformations, the absence of post-polypectomy complications and, consequently, the dramatic reduction of time of patient's admission in the hospital. In fact, all patients were discharged after two hours from polypectomy, thus implying a better quality of life for patients, in the absence of postoperative complications and a reduction of non-medical costs.

Osteoclasts are the sole bone resorbing cells. These cells are essential for skeletal development and remodeling throughout the life of animal and man. Deficiency of osteoclasts leads to osteopetrosis, a diseases manifested by increased non-remodeled bone mass, which ultimately leads to bone deformities and functional failure of other body systems. On the other hand, increased number and activity of osteoclasts under certain pathologic conditions causes accelerated bone resorption and may lead to osteoporosis and osteolytic diseases. To better understand the mechanisms underlying osteoclast- based diseases and design relevant therapies, one should unveil the molecular basis of osteoclast differentiation and function and regulatory mechanisms of osteoclast signaling. This review will outline up-to-date information regarding osteoclast differentiation and activation. Molecular mechanisms underlying osteoclast signaling pathways in inflammatory osteolysis and arthritis will be discussed. In addition, stimulators and inhibitors of osteoclasts, as well as current therapies for osteoclast activity will be addressed.