Showing papers in "Current Drug Targets in 2005"

The ErbB receptors and their ligands in cancer: an overview.

Abstract: This review article provides an overview on the most recent advances on the role of ErbB receptors and growth factors of the epidermal growth factor (EGF)-family of peptides in cancer pathogenesis and progression. The ErbB tyrosine kinases and the EGF-like peptides form a complex system. In fact, the interactions occurring between receptors and ligands of these families affect the type and the duration of the intracellular signals that derive from receptor activation. Interestingly, activation of ErbB receptors is also driven by different classes of membrane receptor, suggesting that ErbB kinases can amplify growth promoting signals carried by different pathways. The importance of ErbB receptors and EGF-like peptides in development of organs and tissues has been demonstrated by using different mouse models. In vitro and in vivo studies have also shown that ErbB receptors and their ligands can act as transforming genes. However, evidence suggests that cooperation of different receptors and ligands is necessary to induce a fully transformed phenotype. Indeed, co-expression of different ErbB receptors and EGF-like growth factors is a common phenomenon in human primary carcinomas. This observation suggests that the growth and the survival of carcinoma cells is sustained by a network of receptors/ligands of the ErbB family. In this respect, the contemporary expression of different ErbB tyrosine kinases and/or EGF-like growth factors in human carcinomas might also affect tumor response to target based agents directed against the ErbB receptor/ligand system.

Systemic fungal infections caused by Candida species: epidemiology, infection process and virulence attributes.

Abstract: Candida species, in particular C. albicans, represent a major threat to immunocompromised patients. Able to exist as a commensal on mucosal surfaces of healthy individuals, these opportunistic fungi frequently cause superficial infections of mucosae and skin. Furthermore, in hospital settings, Candida species may cause life-threatening invasive infections in a growing population of vulnerable patients. In fact, candidaemia is associated with the highest crude mortality of all bloodstream infections. Candida cells may enter the bloodstream by direct penetration from epithelial tissues, due to damage of barriers in the body caused by surgery, polytrauma or drug treatment, or may spread from biofilms produced on medical devices. From the bloodstream, cells may infect almost all organs but appear to prefer certain organs depending upon the route of infection. The exact mechanisms by which Candida cells survive the challenge of the blood environment and escape from the bloodstream to cause deep-seated infections have not yet been elucidated, but various investigations are reviewed. It is clear, however, that Candida must have particular attributes which enable the organism to survive and grow within the environment of healthy individuals and to invade tissues in the immunocompromised host. Most studies have focussed on C. albicans and this review will therefore summarise work on the various known virulence factors and methods used to identify further virulence attributes of this fungus.

Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress.

Abstract: Retinal neovascularization and macular edema are central features of diabetic retinopathy, a major cause of blindness in working age adults. The currently established treatment for diabetic retinopathy targets the vascular pathology by laser photocoagulation. This approach is associated with significant adverse effects due the destruction of neural tissue and is not always effective. Characterization of the molecular and cellular processes involved in vascular growth and hyperpermeability has led to the recognition that the angiogenic growth factor and vascular permeability factor VEGF (vascular endothelial growth factor) play a pivotal role in the retinal microvascular complications of diabetes. Thus, VEGF represents an important target for therapeutic intervention in diabetic retinopathy. Agents that directly inhibit the actions of VEGF and its receptors show considerable promise, but have not proven to be completely effective in blocking pathological angiogenesis. Therefore, a better understanding of the molecular events that control VEGF expression and mediate its downstream actions is important to define more precise therapeutic targets for intervention in diabetic retinopathy. This review highlights the current understanding of the process by which VEGF gene expression is regulated and how VEGF's biological effects are altered during diabetes. In particular, cellular and molecular alterations seen in diabetic models are considered in the context of high glucose-mediated oxidative stress effects on VEGF expression and action. Potential therapeutic strategies for preventing VEGF overexpression or blocking its pathological actions in the diabetic retina are considered.

Serotonin (5-HT) drugs: effects on appetite expression and use for the treatment of obesity.

Abstract: The pivotal role of 5-HT in the control of appetite was formally proposed nearly 30 years ago. In particular endogenous hypothalamic 5-HT has been implicated in the processes of within meal satiation and the end state of post meal satiety. Of the numerous 5-HT receptor subtypes currently identified, 5-HT(1B) and 5-HT(2C) receptors are believed to mediate the 5-HT induced satiety. 5-HT drugs such as d-fenfluramine, selective serotoninergic reuptake inhibitor (SSRIs) and 5-HT(2C) receptor agonists have all been shown to significantly attenuate rodent body weight gain, an effect strongly associated with marked hypophagia. D-Fenfluramine, sibutramine, fluoxetine and the 5-HT(2C) receptor agonist mCPP have also all been shown to reduce caloric intake by modifying appetite in both lean and obese humans. Specifically, 5-HT drugs reduce appetite prior to and after the consumption of fixed caloric loads, and reduce pre meal appetite and caloric intake at ad libitum meals. Clinically significant weight loss over a year or more can be produced by both d-fenfluramine and sibutramine treatment, but apparently not by the SSRI fluoxetine. Treatment with the preferential 5-HT(2C) receptor agonist mCPP and the serotonin precursor 5-HTP has also been shown to produce weight loss in the obese. Issues around the actual and possible side effects of these compounds, and in the case of d-fenfluramine toxicity, have led to a search for drugs that act selectively on the CNS 5-HT receptors critical to the satiety response. Currently, a new generation of 5-HT(2C) selective agonists have been developed (including Ro 60-0175, Org 12962, VER-3323, BVT-933 and YM348) and at least one, ADP356, is currently undergoing clinical trials. Hopefully, such drugs will be as or even more effective at regulating appetite and controlling body weight, and will also be free of their predecessors' side effect.

Ghrelin and Energy Balance: Focus on Current Controversies

Abstract: Ghrelin is an enteric peptide that is the only known circulating appetite stimulant. This feature of the hormone has garnered widespread attention, as reflected by more than 1000 scientific papers featuring ghrelin that have been published since the first reports of its orexigenic actions, approximately four years ago. In this review, we discuss data that support roles for ghrelin in the short-term regulation of pre-meal hunger and meal initiation, functioning as a unique orexigenic counterpart to short-acting gastrointestinal satiation factors, such as cholecystokinin (CCK). We also highlight evidence indicating that ghrelin satisfies recognized criteria to be viewed as a participant in long-term body-weight regulation - a potential anabolic counterpart to the traditional adiposity hormones, leptin and insulin. We then discuss the following controversial questions in ghrelin research and offer our opinions regarding these debates. (1) Is ghrelin synthesized within the brain? (2) How does ghrelin increase food intake? (3) Does des-acyl ghrelin have a physiologic function? (4) Are there receptors for ghrelin other than GHS-R1a? (5) Does ghrelin regulate insulin secretion? (6) Does ghrelin regulate gastrointestinal motility? (7) Can ghrelin or ghrelin-receptor agonists be used to treat wasting conditions? Finally, we offer a speculative model of ghrelin as a thrifty gene product that evolved to help animals consume and store fat well, thereby increasing their chances of survival during times of famine. We suggest that ghrelin is a “saginary” hormone, from the Latin, saginare, which means, “to fatten”.

Systemic fungal infections caused by Aspergillus species: epidemiology, infection process and virulence determinants.

Abstract: Infections with mould pathogens have emerged as an increasing risk faced by patients under sustained immunosuppression. Species of the Aspergillus family account for most of these infections and in particular Aspergillus fumigatus can be regarded as the most important airborne-pathogenic fungus. The improvement in transplant medicine and the therapy of hematological malignancies is often complicated by the threat of invasive aspergillosis. Specific diagnostics are still limited, as are the possibilities of therapeutic intervention. Hence, invasive aspergillosis is still associated with a high mortality rate that ranges from 30 % to 90 %. In recent years, considerable progress has been made in understanding the genetics of A. fumigatus and molecular techniques for the manipulation of the fungus have been developed. Molecular genetics offers not only approaches for the detailed characterization of gene products that appear to be key components of the infection process but also selection strategies that combine classical genetics and molecular biology to identify virulence determinants of A. fumigatus. The review discusses aspects of the current knowledge of the infection process, mechanisms of protection of the fungus against immune effector cells, and virulence determinants of A. fumigatus.

The role of AGEs and AGE inhibitors in diabetic cardiovascular disease.

Abstract: Prolonged hyperglycemia, dyslipidemia and oxidative stress in diabetes result in the production and accumulation of AGEs. It is now clear that AGEs contribute to the development and progression of cardiovascular disease in diabetes, as well as other complications. AGEs are thought to act through receptor-independent and dependent mechanisms to promote vascular damage, fibrosis and inflammation associated with accelerated atherogenesis. As a result, novel therapeutic agents to reduce the accumulation of AGEs in diabetes have gained interest as potential cardioprotective approaches. A variety of agents have been developed which are examined in detail in this review. These include aminoguanidine, ALT-946, pyridoxamine, benfotiamine, OPB-9195, alagebrium chloride, N-phenacylthiazolium bromide and LR-90. In addition, it has been demonstrated that a number of established therapies have the ability to reduce the accumulation of AGEs in diabetes including ACE inhibitors, angiotensin receptor antagonists, metformin, peroxisome proliferators receptor agonists, metal chelators and some antioxidants. The fact that many of these inhibitors of AGEs are effective in experimental models, despite their disparate mechanisms of action, supports the keystone role of AGEs in diabetic vascular damage. Nonetheless, the clinical utility of AGE inhibition remains to be firmly established. Optimal metabolic and blood pressure control, that is achieved early and sustained indefinitely, remains the best recourse for inhibition of AGEs until more specific interventions become a clinical reality.

Colloidal carriers for ophthalmic drug delivery.

Abstract: To achieve effective drug concentration at the intended site for a sufficient period of time is a requisite desired for many drug formulations. For drugs intended to ocular delivery, its poor bioavailability is due to pre-corneal factors. Most ocular diseases are treated by topical drug application in the form of solution, suspension and ointment. However, such dosage forms are no longer sufficient to combat some ocular diseases. Intravitreal drug injection is the current therapy for disorders in posterior segment. The procedure is associated with a high risk of complications, particularly when frequent, repeated injections are required. Thus, sustained-release technologies are being proposed, and the benefits of using colloidal carriers in intravitreal injections are currently under investigation for posterior drug delivery. This review will discuss recent progress and specific development issues relating to colloidal drug delivery systems, such as liposomes, niosomes, nanoparticles, and microemulsions in ocular drug delivery.

Aldose reductase in diabetic microvascular complications.

Abstract: Most long-term diabetic patients develop microvascular diseases such as retinopathy, nephropathy and neuropathy. Although tight control of blood glucose greatly reduces the incidence of these complications, a significant fraction of diabetic patients with good glycemic control still develop these diseases. Therefore, it is imperative to understand the underlying mechanisms of these diseases such that effective treatment or preventive methods can be developed to augment euglycemic control. In animal studies, there is strong evidence that aldose reductase, the first and rate-limiting enzyme of the polyol pathway that converts glucose to fructose, plays a key role in the pathogenesis of microvascular complications. However, clinical trials of the aldose reductase inhibitors were disappointing and several pharmaceutical companies had abandoned the development of this line of drugs. In this review, the potential pathogenic mechanisms of the polyol pathway are presented, the evidence for the involvement of the polyol pathway in diabetic complications summarized, and the reasons for the unimpressive results of the clinical trials of the aldose inhibitors discussed. It appears that renewed efforts to develop aldose reductase inhibitors for the treatment and prevention of diabetic complications are warranted.

Pancreatic amylin as a centrally acting satiating hormone.

Abstract: This review summarizes the present knowledge concerning the anorectic action of the pancreatic hormone amylin. It focuses mainly on the role of amylin as a short term satiating peptide. Since there is some evidence however that basal amylin levels might play a role in the long term control of food intake and/or body weight, this aspect will be discussed briefly towards the end of this review. Concerning amylin as a satiating hormone, it is well established that amylin is released during meals, and that exogenous amylin leads to a dose-related reduction in meal size. Amylin has a rapid onset and brief duration of action. The area postrema (AP) plays a predominant role in peripheral amylin's satiating effect, involving a direct activation of AP neurons by blood-borne amylin. The nucleus of the solitary tract (NTS) relays this effect to higher brain structures, the lateral parabrachial nucleus, and possibly the central nucleus of the amygdala and the bed nucleus of the stria terminalis. Amylin's anorectic effect may in part be due to reduced expression of orexigenic neuropeptides in the lateral hypothalamic area. The anorectic action of amylin is one important factor in amylin's overall role to control the influx of nutrients into the circulation. By reducing food intake, gastric acid secretion, limiting the rate of gastric emptying and diminishing pancreatic glucagon and digestive enzyme secretion, amylin regulates nutrient appearance and postprandial glucose concentration. Amylin seems to be a necessary and complementary factor to insulin, which regulates the rate of nutrient disappearance. In this sense, amylin and insulin are adjunct players in the control of nutrient fluxes, and amylin's role to control feeding is a pivotal factor in this regard.

Phenothiazinium based photosensitisers--photodynamic agents with a multiplicity of cellular targets and clinical applications.

Abstract: Phenothiazinium based photosensitisers (PhBPs) possess planar heteroaromatic ring structures that give the parent molecules photosensitising properties. PhBPs show potential application in photodynamic therapy (PDT) as antitumour agents, and in photodynamic chemotherapy (PACT) as antimicrobial compounds. PhBPs show selectivity for tumour and microbial cells, which appears to be based on electrostatic interactions between the positive charge generally carried by these molecules and the negative charge found on the outer surface of these target cells. In some cases, a site of action for photoactivated PhBPs is the outer membrane / envelope of the target cell. Such action can involve the modification of membrane lipid and / or lipopolysaccharide, and the inactivation of essential proteins and enzymes, with these effects usually leading to cell lysis and death. However, more often, PhBPs are internalised by target cells, promoted by a variety of factors, including low pH and enzymatic reduction, and upon photoactivation, internalised, PhBPs are able to inflict damage on a number of intracellular targets. In tumour cells, PhBPs can photodamage DNA and the membranes of organelles, thereby inducing necrosis and / or apoptosis. In bacterial cells, whilst DNA is generally a primary target of PhBPs, these compounds can exhibit multiple sites of action within a given cell and show different sites of action between different bacterial species. This variable targeting makes PhBPs attractive propositions as alternatives to conventional antibiotics in that the emergence of bacterial strains with acquired resistance to these compounds appears to be highly unlikely.

Ketamine: New Indications for an Old Drug

Abstract: Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl-d-aspartate (NMDA) receptor for glutamate, though its effects are mediated by interaction with many others receptors. It has been introduced in clinical use since 1960's but today it is not largely employed as a general anaesthetic for its undesired psychic effects (emergence reactions) occurring in approximately 12% of patients. In the last decade, there has been a renewed interest in the use of subanaesthetic doses of ketamine for the treatment of acute and chronic pain. In the late 1990's, multiple prospective, randomised, controlled study has shown the efficacy of low dose of ketamine for postoperative pain relief, for analgesia during regional or local anaesthesia, and for opioid-sparing effect. At present, non-definitive conclusion can be drawn. More data are needed to define the possible long term effects and the clinical goal of ketamine use.

Peptide YY: A Potential Therapy for Obesity

Abstract: Obesity now represents a modern epidemic in western society with major health and economic consequences. Unfortunately, previous pharmacological approaches to the treatment of obesity have been associated with life-threatening side effects and limited efficacy. Over recent years there has been a marked increase in our understanding of the physiological mechanisms that regulate body weight and how these are perturbed in obesity. One therapeutic strategy is to develop drugs which both mimic and enhance the body's own satiety signals. The gut hormone peptide tyrosine tyrosine (PYY), which is released postprandially from the gastrointestinal tract, has recently been shown to be a physiological regulator of food intake. Peripheral administration of PYY reduces feeding in rodents via a mechanism which requires the Y2 receptor and is thought to primarily involve modulation of the hypothalamic arcuate nucleus (ARC) circuitry. In humans a single 90-minute infusion of PYY has been shown to markedly reduce subsequent 24-hour caloric intake in lean, normal-weight and obese subjects. Moreover, obese subjects have been found to have low levels of fasting and postprandial PYY suggesting a role for this hormone in the pathogenesis of obesity. Although studies examining the effects of chronic peripheral administration of PYY to humans are awaited, the results from continuous infusion studies in a number of obese rodent models are encouraging with reductions in food intake, body weight and adiposity observed. Potential therapeutic manipulations based on the PYY system include development of Y2 agonists, exogenously administration of PYY or increased endogenous release from the gastrointestinal tract.

NAD(P)H oxidase activation: a potential target mechanism for diabetic vascular complications, progressive beta-cell dysfunction and metabolic syndrome.

Abstract: Both protein kinase C (PKC) activation and increased oxidative stress have been paid attention to as important causative factors for diabetic vascular complications. In this article, we show a PKC-dependent increase in oxidative stress in vascular tissues of diabetes and insulin resistant state. High glucose level and free fatty acids stimulate de novo diacylglycerol (DAG)-PKC pathway and subsequently stimulate reactive oxygen species (ROS) production through a PKC-dependent activation of NAD(P)H oxidase. Increasing evidence has also shown that NAD(P)H oxidase components are upregulated in micro- and macro- vascular tissues of animal models and patients of diabetes and obesity. It is also noted that increased intrinsic angiotensin II production may amplify such a PKC-dependent activation of NAD(P)H oxidase in diabetic vascular tissues. These mechanisms may play an important role in the diabetic vascular complications and the accelerated atherosclerosis associated with diabetes and obesity. In addition, recent reports have shown that NAD(P)H oxidases exist in pancreatic beta-cells and adipocytes, and this oxidase-generated ROS production may play an important role in both the progressive beta-cell dysfunction and the dysregulated adipocytokine production and subsequent obesity-induced metabolic syndrome. These results suggest that an NAD(P)H oxidase activation may be a useful therapeutic target for preventing diabetic vascular complications, progressive beta-cell dysfunction and metabolic syndrome.

Targeted agents for the treatment of advanced renal cell carcinoma.

Abstract: Renal cell carcinoma (RCC) is a highly treatment-resistant tumor type; however, advances in elucidating the molecular pathophysiology underlying RCC has led to the identification of promising targets for therapeutic intervention. In clear-cell RCC, mutations to the von Hippel-Lindau (VHL) gene results in the up regulation of many proteins necessary for tumor growth and survival--such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF), which are involved in tumor-initiated angiogenesis. Carbonic anhydrase IX and signaling via the epidermal growth factor receptor (EGFR) are involved in tumor cell proliferation and are also up regulated by mutation in the VHL gene. The intracellular messenger pathways phosphoinositide 3-kinase (PI3K) and Raf/MEK/ERK act as convergence points for positive growth signaling; the Raf/MEK/ERK pathway is also implicated in apoptosis. Several agents in development target VEGF (bevacizumab), the VEGF receptor (PTK787, SU11248, VEGF-trap, and BAY 43-9006), the PDGF receptor (SU11248 and BAY 43-9006), or the EGF receptor (gefitinib, cetuximab, ABX-EGF, and erlotinib). The intracellular Raf/MEK/ERK signaling cascade has been targeted at either the level of Raf (BAY 43-9006, ISIS 5132) or MEK (CI-1040, PD184352 and ARRY-142886), and PI3K signaling is disrupted by CCI-779. WX-G250 targets the G250 antigen, and PS-341 disrupts the 26S proteasome mediating the degradation of intracellular proteins. Given that multiple pathways contribute to tumor growth, anti-tumor activity may be increased by agents targeting multiple pathways, or by combining agents to allow horizontal or vertical inhibition of multiple pathways.

Stem cell therapy for neurologic disorders: therapeutic potential of adipose-derived stem cells.

Abstract: There is growing evidence to suggest that reservoirs of stem cells may reside in several types of adult tissue. These cells may retain the potential to transdifferentiate from one phenotype to another, presenting exciting possibilities for cellular therapies. Recent discoveries in the area of neural differentiation are particularly exciting given the limited capacity of neural tissue for intrinsic repair and regeneration. Adult adipose tissue is a rich source of mesenchymal stem cells, providing an abundant and accessible source of adult stem cells. These cells have been termed adipose derived stem cells (ASC). The characterization of these ASCs has defined a population similar to marrow-derived and skeletal muscle-derived stem cells. The success seen in differentiating ASC into various mesenchymal lineages has generated interest in using ASC for neuronal differentiation. Initial in vitro studies characterized the morphology and protein expression of ASC after exposure to neural induction agents. Additional in vitro data suggests the possibility that ASCs are capable of neuronal activity. Progress in the in vitro characterization of ASCs has led to in vivo modeling to determine the survival, migration, and engraftment of transplanted ASCs. While work to define the mechanisms behind the transdifferentiation of ASCs continues, their application to neurological diseases and injuries should also progress. The subject of this review is the capacity of adipose derived stem cells (ASC) for neural transdifferentiation and their application to the treatment of various neurologic disorders.

Drugging cell cycle kinases in cancer therapy.

Abstract: Cell cycle kinases are comprised of cyclin-dependent kinases (Cdks), non-Cdk kinases such as Plk-1 and Aurora and checkpoint proteins such as Chk1 and Chk2. Though ubiquitous to dividing cells, many cell cycle kinases are amplified or over-expressed in malignancy and are potential targets for anti-cancer therapies. Cdk inhibiting drugs (such as flavopiridol, UCN-01, E7070, R-Roscovitine and BMS-387032) have shown preclinical and clinical anticancer activity. However, many of these agents are promiscuous and undiscerning, targeting other non-cell cycle kinases and affecting normal cells, thereby causing significant toxicity. To overcome this, a new generation of Cdk inhibitors are in development with greater target specificity, as well as others that inhibit non-Cdk cell cycle kinases, both directly and indirectly. The outcome of early clinical trials involving these agents is awaited, but these certainly represent a promising new area of anticancer drug development.

Endogenous and exogenous CNS derived stem/progenitor cell approaches for neurotrauma.

Abstract: Neural stem/progenitor cells capable of generating new neurons and glia, reside in specific areas of the adult mammalian central nervous system (CNS), including the ependymal region of the spinal cord and the subventricular zone (SVZ), hippocampus, and dentate gyrus of the brain. Much is known about the neurogenic regions in the CNS, and their response to various stimuli including injury, neurotrophins (NFs), morphogens, and environmental factors like learning, stress, and aging. This work has shaped our current views about the CNS's potential to recover lost tissue and function post-traumatically and the therapies to support the intrinsic regenerative capacity of the brain or spinal cord. Recently, intensive research has explored the potential of harvesting, culturing, and transplanting neural stem/progenitors as a therapeutic intervention for spinal cord injury (SCI) and traumatic brain injury (TBI). Another strategy has focused on maximizing the potential of this endogenous population of cells by stimulating their recruitment, proliferation, migration, and differentiation in vivo following traumatic lesions to the CNS. The promise of such experimental treatments has prompted tissue and biomaterial engineers to implant synthetic three-dimensional biodegradable scaffolds seeded with neural stem/progenitors into CNS lesions. Although there is no definitive answer about the ideal cell type for transplantation, strong evidence supports the use of region specific neural stem/progenitors. The technical and logistic considerations for transplanting neural stem/progenitors are extensive and crucial to optimizing and maintaining cell survival both before and after transplantation, as well as for tracking the fate of transplanted cells. These issues have been systematically addressed in many animal models, that has improved our understanding and approach to clinical therapeutic paradigms.

Molecular targets of diabetic cardiovascular complications.

Abstract: Both the macro- and microvascular complications adversely affect the life quality of patients with diabetes and have been the leading cause of mortality and morbidity in this population. With the advancement of technologies in biomedical research, we have gained a great deal of understanding of the mechanisms underlying these complications. While euglycemic control still remains the best strategy, it is often difficult to maintain at a level that can completely prevent the vascular complications. Therefore, it is necessary to use the processes leading to vascular dysfunction as a framework for designing novel molecular therapeutic targets. Several of the mechanisms by which diabetes induces vascular complications include increased flux through the polyol pathway, increased oxidative stress, activation of protein kinase C (PKC), vascular inflammation, and abnormal expression and actions of cytokines in the vasculature. Many of the therapies that target these pathways have proven successful in experimental models of diabetic complications. However, clinical studies using these treatments have mainly yielded inconclusive results. The pathogenesis of diabetic vascular complications and results from animal studies and key clinical studies are reviewed here.

Decreasing the metastatic potential in cancers--targeting the heparan sulfate proteoglycans.

Abstract: The heterogeneity of proteoglycans (PG)s contributes to their functional diversity. Many functions depend on their ability to bind and modulate the activity of components of the extracellular matrix (ECM). The ability of PGs to interact with other molecules, such as growth factors, is largely determined by the fine structure of the glycosaminoglycan (GAG) chains. Tumorigenesis is associated with changes in the PG synthesis. Heparan sulfate (HS) PGs are involved in several aspects of cancer biology including tumor progression, angiogenesis, and metastasis. PGs can have both tumor promoting and tumor suppressing activities depending on the protein core, the GAG attached, molecules they associate with, localization, the tumor subtype, stages, and degree of tumor differentiation. Perlecan is an angiogenic factor involved in tumor invasiveness. The C-terminal domain V of perlecan, named endorepellin, has however been shown to inhibit angiogenesis. Another angiogenic factor is endostatin, the COOH-terminal domain of the part-time PG collagen XVIII. Glypicans and syndecans may promote local cancer cell growth in some cancer tissues, but inhibit tissue invasion and metastasis in others. The GAG hyaluronan (HA) promotes cancer growth by providing a loose matrix for migrating tumor cells and mediates adhesion of cancer cells. HSPG degrading enzymes like heparanase, heparitinase, and other enzymes such as hyaluronidase and MMP are also important in tumor metastasis. Several different treatment strategies that target PGs have been developed. They have the potential to be effective in reducing tumor growth and inhibit the formation of metastases. PGs are also valuable tumor markers in several cancers.

The hypothalamus and obesity.

Abstract: Obesity, a condition already at epidemic proportions in the developed world, is largely attributable to an indulgent lifestyle. Biologically we feel hunger more acutely than feeling "full-up" (satiety). The discovery over a decade ago of leptin, an adiposity signal, revolutionised our understanding of hypothalamic mechanisms underpinning the central control of ingestive behaviour. The structure and function of many hypothalamic peptides (Neuropeptide Y (NPY), Melanocortins, Agouti related peptide (AGRP), Cocaine and amphetamine regulated transcript (CART), Melanin concentrating hormone (MCH), Orexins and endocannabinoids) have been characterised in rodent models. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Short-term signal hormones including Cholecystokinin (CCK), Ghrelin, Peptide YY (PYY(3-36)) and Glucagon-like peptide 1 (GLP-1) control meal size via pathways converging on the hypothalamus. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems among others, implicated in hypothalamic appetite regulation all provide potential "drugable" targets by which to treat obesity.

Adipokines: therapeutic targets for metabolic syndrome.

Abstract: For a long time it has been known that obesity (adiposity) is linked to insulin resistance. Recently, many investigators have reported that adipocytes secrete a variety of bioactive molecules, termed adipokines (adipocytokines), including TNFalpha, IL-6, leptin, adiponectin, resistin and so on. These adipokines play pivotal roles in energy homeostasis by affecting insulin sensitivity, glucose and lipid metabolisms, food intake, the coagulation system and inflammation. This review provides a summary of these adipose tissue-secreting biomolecules and discusses their feasibilities as drug targets for the treatment of metabolic syndrome.

Cannabinoids and the regulation of ingestive behaviour.

Abstract: Over past centuries, Cannabis sativa (Delta(9)-tetrahydrocannabinol being the principal active ingredient) has been used extensively for both medicinal and recreational uses, and one widely reported effect is the onset of a ravenous appetite and eating behaviour. The pharmacological properties of such exogenous cannabinoids are mediated through the activation of two receptor subtypes, the CB(1) and CB(2) receptors. A number of endogenous ligands for these receptors, the endocannabinoids, have now also been identified allowing their effects on ingestive behaviour to be determined. In a number of species, including man, the administration of exogenous and endogenous cannabinoids leads to robust increases in food intake and can promote body weight gain. These effects are believed to be mediated through activation of the CB(1) receptor. Conversely, experiments with selective CB(1) receptor antagonists have demonstrated reductions in food intake and body weight with repeated compound administration. These reductions in body weight appear to be greater in obese animals and may be the result of a dual effect on both food intake and metabolic processes. Such findings have led to a number of pharmaceutical companies developing selective CB(1) receptor antagonists for the treatment of obesity. The most advanced compound is Sanofi-Synthelabo's inverse agonist, rimonabant (Acomplia; SR-141716), and early Phase III results have recently demonstrated significant reductions in body weight, waist circumference and improvement of lipid and glucose metabolism in overweight and obese humans. Accordingly, the cannabinoid system appears to have an important role in the regulation of ingestive behaviour in man and animals.

Small molecules with EGFR-TK inhibitor activity.

Abstract: Specific and reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib are clinically active in advanced or metastatic NSCLC and both are approved in various countries for the treatment of patients that failed prior chemotherapy. Erlotinib has also prolonged survival in pancreatic cancer patients when added to gemcitabine and regulatory approval in this disease is being sought. Additional promising activity has been seen in other tumor types, such as ovarian cancer or head and neck malignancies, and phase III trials in these malignancies are ongoing or planned. Despite these successes, these agents have exhibited anecdotal or modest activity when used as single agents in unselected patients with various other tumor types. We have learned that the clinical development of these agents is far from simple and we need to better understand biological and clinical criteria for patient selection and how to best use the different available agents. The recent discovery of EGFR mutations and the potential identification of other markers that might predict patient response could help to optimize the use of these agents in the future. Irreversible EGFR inhibitors, dual EGF/HER2 and pan-ErbB receptor inhibitors may have greater antitumor activity although the tolerance of these compounds compared to specific EGFR TKIs needs further characterization. HER2 specific TKIs are also in development. Lapatinib, a dual EGFR/HER2 TK inhibitors, is particularly promising in breast cancer. Newer agents, such as BMS-599626, have recently entered into the clinic. In addition to the use of these agents as single agents, many clinical studies are addressing the role of combining them with hormonal agents, biological agents or chemotherapy.

Modulation of Eating by Central Catecholamine Systems

Abstract: The focus of the present review is the modulation of eating by the endogenous catecholamines (CA) dopamine (DA) and norepinephrine (NE). Topics addressed include pharmacological and genomic manipulations of brain CA systems and subsequent changes in ingestive behavior. DA in particular is a key component of brain reinforcement systems and feeding-associated changes in DA may play a role in the reinforcing aspects of feeding. NE has been linked to both stimulation and suppression of eating and recent evidence has linked these effects to activation of distinct adrenoceptor subtypes. Recent evidence suggests that NE systems may interact with DA systems to augment the activational effects of psychostimulant drugs, such as cocaine or amphetamine, and DA/NE interactions may play a key role in the capacity of psychostimulants to suppress eating.

Adult stem cell application in spinal cord injury.

Abstract: The mechanical force incurred by spinal cord injury results in degenerative neural tissue damage beyond the site of initial injury. By nature, the central nervous system (CNS) does not regenerate itself. Cell therapy, in particular, stem cell implantation has become a possible solution for spinal cord injury. Embryonic stem cells and fetal stem cells are the forefathers of the field of stem cell therapy. Isolation and preparation of specific populations of adult stem cells have evolved to the point of stable, long-term culturing with the capability to differentiate into neural phenotypes from all three of the neural lineages: neurons, astrocytes, and oligodendrocytes. Thus, adult stem cells will transcend ethical concerns, technical difficulties, and probably immunorejection. A variety of adult stem cells have been implanted in a rat model of spinal cord injury, ranging from olfactory ensheathing cells, cultured spinal cord stem cells, bone marrow derived stem cells, dermis derived stem cells, and a few others. Although no definite decisions on which adult stem cells are most effective for this CNS injury, their ability to incorporate into the spinal cord, differentiate, and to improve locomotor recovery hold promise for a cure.

Integral therapeutic potential of bone marrow mesenchymal stem cells.

Abstract: Bone marrow derived mesenchymal stem cells (MSC) are adult stem cells that reside within the bone marrow compartment. In the traditional developmental model, adult stem cells are able to differentiate only to the tissue in which they reside. Recent data have challenged the committed fate of the adult stem cells, presenting evidence for their multi-lineage differentiation potential. In addition, potential therapeutic benefits of MSC administration have been the main concern of much research, including clinical trials. These studies promote adult stem cell therapy by shedding some light on the therapeutic potential of MSC and their mechanism of action. Many doubts have found their way into MSC research. They question MSC potency and beneficial contribution. However, these obstacles should not arrest but set a challenge to MSC researchers to examine their achievements under a magnifying glass. Therapeutic benefits of MSC exogenous delivery do not run counter to its possible participation in endogenous repair. Several reports imply MSC involvement in physiological repair but no explicit data support this hypothesis. This review tries to put MSC research into perspective. Possible therapeutic applications of MSC therapy for damaged tissue replacement, tissue engineering and the underlying repair mechanisms will be discussed. In addition, reported data about MSC possible involvement in physiological multiple tissue repair, their homing to injury and site-specific differentiation will be presented.

Fungal Infections of the Skin: Infection Process and Antimycotic Therapy

Abstract: Dermatomycoses are among the most widespread and common superficial and cutaneous fungal infections in humans These typically nonfatal conditions are difficult to treat, especially infections of the nail Dermatomycoses are caused by filamentous fungi such as Trichophyton, Microsporum or Epidermophyton species These filamentous fungi have a high affinity for keratin, an important component of hair, skin and nails, which are the primary areas of infection by dermatophytes The antifungal agents currently marketed for dermatomycoses are mainly inhibitors of ergosterol biosynthesis, except for griseofulvin, which interferes with the cytoplasmic and nuclear microtubular system Three different types of inhibitors of the ergosterol biosynthetic pathway have been proven to be effective in clinic: the azoles (eg topical miconazole and topical/oral ketoconazole, itraconazole and fluconazole), the allylamines (eg terbinafine) and morpholines (amorolfine) Even today more effective antifungal azoles with less adverse effects and short-term therapy are deemed necessary to treat dermatophytosis A promising novel triazole compound in this respect is R126638, which showed potent in vitro and in vivo activity

Fungal biofilms and antimycotics.

Abstract: Device-related infections in most nosocomial diseases can be traced to the formation of biofilms (microbial communities encased within a polysaccharide-rich extracellular matrix) by pathogens on surfaces of these devices. Candida species are the most common causative agents of these infections, and biofilms formed by these fungal organisms are associated with drastically enhanced resistance against most antimicrobial agents. This enhanced resistance contributes to the persistence of this fungus despite antifungal therapy. Recent studies showed that Candida biofilms exhibit antifungal resistance against most antifungal agents with the exception of echinocandins and lipid formulations of AMB. This review discusses methods used to evaluate biofilm resistance and provide information on susceptibility pattern of candidal biofilm as well as studies investigating the mechanisms underlying biofilm resistance.

Isoprenylation of intracellular proteins as a new target for the therapy of human neoplasms: preclinical and clinical implications.

Abstract: Cell proliferation, differentiation, and survival are regulated by a number of extracellular hormones, growth factors, and cytokines in complex organisms. The transduction of the signals by these factors from the outside to the nucleus often requires the presence of small intracellular proteins (i.e. ras and other small G proteins) that are linked to the plasma membrane through a isoprenyl residue that functions as hydrophobic anchor. Isoprenylation is a complex process regulated by different enzymatic steps that could represent potential molecular targets for anti-cancer strategies. In the present paper the different transduction pathways regulated by some isoprenylated proteins such as ras and other small G proteins are described. Moreover, the molecular mechanisms of the isoprenylation process and the mode of action of the different isoprenylation inhibitors are discussed with attention to statins, farnesyltransferase inhibitors (FTI) and aminobisphosphonates. The role of different candidate targets in the determination of anti-tumour effects by FTIs is also described in order to define potential molecular markers predictor of clinical response. On the basis of several preclinical data, new strategies based on multi-step enzyme inhibition or on target prioritization are proposed in order to enhance the anti-tumour activity of agents inhibiting isoprenylation. Finally, a summary of the principal data on clinical trials based on the use of FTIs and statins is given. In conclusion, the inhibition of isoprenylation is an attractive, but still not completely investigated therapeutic alternative that requires optimization for the translation in the current treatment of neoplasms.