Current Medicinal Chemistry - Volume 17, Issue 23, 2010

Red wine contains many compounds that may have therapeutic use, including resveratrol (3,4',5-trihydroxytrans- stilbene). Since resveratrol could be administered both in the diet and as a therapeutic agent, defining appropriate concentrations requires understanding of the pharmacokinetics. Resveratrol absorption is rapid but plasma concentrations are low as it is rapidly and efficiently converted into relatively hydrophilic phase-2 conjugates, and metabolites, which are then rapidly excreted via the urine and bile. Resveratrol is an effective antioxidant in vivo by increasing NO synthesis and also maintaining the reduced intracellular redox state via the thioredoxin system. Further, activation of sirtuins (one class of lysine deacetylases) may mediate the cardiovascular responses shown by resveratrol. Studies on animal models of human disease suggest that resveratrol has the potential to decrease cardiovascular symptoms in patients with myocardial infarction, arrhythmias, hypertension, cardiomyopathies, fibrosis, atherosclerosis, thrombosis and diabetes, but, as yet, human clinical trials are rare. Cardioprotection by resveratrol in rodent models may rely on mechanisms producing pharmacological preconditioning in the heart including reducing reactive oxygen species, improving vasorelaxation and angiogenesis, preventing inflammation and apoptosis, delaying atherosclerosis as well as decreasing cardiovascular remodelling. Interventional studies in humans need to be completed before resveratrol can be considered as a standard therapeutic agent. Therefore, future studies should focus on obtaining the level of evidence required to determine whether resveratrol can be added to the list of evidence-based therapies for cardiovascular diseases that includes renin-angiotensin system inhibitors, β-adrenoceptor antagonists and calcium entry blockers.

For many years, the purine salvage pathway of parasitic protozoa has been regarded as an attractive chemotherapeutic target. Parasitic protozoa lack de novo synthesis and rely entirely on the purine salvage pathway to meet their purine demands. Because of the great phylogenetic difference between parasite and host, there are often sufficient distinctions that can be exploited to design specific inhibitors for the parasitic enzymes. As a result, this pathway has been thoroughly investigated over the last twenty years. It is only quite recently that the genome studies of Trypanosoma, Leishmania and Plasmodium have been published. Based on these genomic data however, the existence of by-pass mechanisms by other enzymes and transporter systems could be suggested. Taking into account such proposition, the question might arise as to whether inhibition of a single salvage enzyme will be able or not to cause parasite death or growth arrest. In this paper, the key enzymes in the purine salvage pathways of relevant pathogenic species from the genera Trypanosoma, Leishmania and Plasmodium are reviewed. Their potential as drug targets is critically evaluated and where possible, correlated to literature data on antiparasitic activity of their inhibitors. While many studies over the past ten years have yielded contradictory results, this review attempts to clarify these findings by discussing the latest elements of progress in the field. Additionally, as part of a broader discussion on substrate analogue types of inhibitors, special attention is paid to iminoribitol derivatives, serving as transition state analogues of nucleoside-processing enzymes and comprising the most potent inhibitors reported for purine salvage enzymes. More specifically, the development of three generations of immucillins and a newer series of N-(arylmethyl-) substituted iminoribitol derivatives will be discussed. Finally, this review also covers subversive substrates of salvage enzymes: compounds that are transformed by enzymatic activity into cytotoxic agents. Although not by directly intervening in the process of purine recovery, the subversive substrate approach might deliver antiprotozoal compounds that rely on salvage enzymes for their activity.

Huntington's disease (HD) is a genetic neurodegenerative process whose etiology is based on a localized disturbance in the short arm of chromosome 4 that encodes the huntingtin protein (Htt). The elongation of triple CAG for glutamine characterizes this change. Mutated Htt (mHtt) causes the appearance of intracellular aggregates inducing alterations in mitochondrial metabolism in the form of reactive oxygen species (ROS) and ATP depletion. The oxidative imbalance caused by mHtt leads the neurons to a state of oxidative stress resulting in damage to macromolecules and cellular death. Since the discovery of certain mechanisms underlying the pathogenesis of HD, several therapeutic procedures have been shown to delay or slow the evolution of the condition and have demonstrated the biochemical and molecular mechanism involved. The studies have reported that transcranial magnetic stimulation (TMS) may improve motor and other symptoms associated with neurodegenerative and neuropsychiatric processes such as major depression, schizophrenia, epilepsy, neuropathic pain, amyotrophic lateral sclerosis, progressive muscle atrophy, multiple sclerosis, stroke, Alzheimer's disease, Parkinson's disease or HD. This study focuses on the effect of TMS on oxidative stress and neurogenesis in studies and its possible usefulness in HD.

Positron emission computed tomography (PET) is a functional, noninvasive method for imaging regional metabolic processes that is nowadays most often combined to morphological imaging with computed tomography (CT). Its use is based on the well-founded assumption that metabolic changes occur earlier in tumors than morphologic changes, adding another dimension to imaging. This article will review the established and investigational indications and radiopharmaceuticals for PET/CT imaging for prostate cancer, bladder cancer and testicular cancer, before presenting upcoming applications in radiation therapy.

The anticoagulant behavior of sulfated polysaccharides from seaweeds is reviewed based on their chemical structures. Analysis of the literature suggested that the driving force for the formation of the sulfated polysaccharide/ protein complex is the non-specific polar interaction between the negatively and positively charged groups in the polysaccharide and protein, respectively and that the complex is further stabilized by short-range interactions. The polysaccharide binding site should be able to go through the following conformational steps in the formation of the complex: random coil→ordered conformation→low distortion of this conformation to form a complementary fitting structure with the protein backbone. The sulfated monosaccharide units with the highest potential for anticoagulant activity should have two sulfate groups and a glycosidic linkage on the pyranose ring with C-2, C-3 and C-4 in 2S, 3R, 4R or 2R, 3S, 4S configurations for galactose, fucose and arabinose and 2S, 3S, 4R, for rhamnose. Three distributions of these substituents appear: 3-linked 2,4-disulfated units, 4-linked 2,3-disulfated units and 2-linked 3,4-disulfated residues. These types of units have the possibility, through the equilibrium of the chair conformations, to place their sulfate groups in adequate spacial positions to interact with basic groups of the protein. The anticoagulant activity is mainly attributed to thrombin inhibition mediated by antithrombin and/or heparin cofactor II, with different effectivenesses depending of the compound. Other mechanisms are also proposed and these differences could be attributed to the diversity of structures of the polysaccharides evaluated and to the fact that one compound may have more than one target protease.

Hirsutism is the presence of excess hair growth in women in the typical male hair growth areas, thereby reflecting a deviation from the normal female hair pattern. It affects from 5% to 10% of women, depending on age, menopausal status and ethnic background. The presence of hirsutism is very distressing for women, and subsequently may have a negative impact on their psychosocial life. In the treatment of hirsutism several options are now available, including pharmacologic regimens and cosmetic measures. Both the hormonal profile of the patient and her expectations and preferences should guide the therapeutic approach. The aims of the medical therapy are suppression of excessive androgen production, inhibition of peripheral action of androgens, and treatment of patients at risk for metabolic disorders or reproductive cancers. For other diseases related to endocrine abnormalities, such as thyroid disorders or Cushing's syndrome, specific treatment is mandatory. After an ineffective local approach by direct hair removal, a pharmacological treatment should be suggested, using estrogen and progestin combinations, antiandrogens (i.e. cyproterone acetate, spironolactone) or both as a first line. Finasteride, gonadotropin-releasing hormone agonists, and glucocorticoids should be used in selected cases. Adequate contraception is also recommended if antiandrogens are used. Unfortunately, since systemic therapy reduces hair growth in less than 50% of cases, hirsute women frequently require cosmetic measures. The use of a logical combination of different options has been shown to achieve a satisfactory result in most cases. This review provides information and suggestions about the current options of treating hirsutism.

Reactive oxygen species (ROS) generated by cigarette smoke may contribute to lung and oral cancer. The 18 kDa Translocator protein (TSPO) has been reported to be affected by ROS as well as to participate in ROS generation at mitochondrial levels, and has been implicated in pro-apoptotic and anti-carcinogenic functions. The present study reports the presence of TSPO in the cellular fraction of human saliva. In cells collected from untreated saliva, the specific TSPO ligand [3H]PK 11195 showed saturable binding with high affinity, with mean Bmax and Kd values of 6,471 ± 501 fmol/mg protein and 6.2 ± 0.5 nM, respectively. Our study further indicates that the cellular fraction of human saliva possesses TSPO with binding characteristics similar to that of cells from other tissues of human origin. Following exposure of saliva to cigarette smoke a three-fold decrease in the affinity of salivary TSPO to its specific ligand, [3H]PK 11195 (p < 0.01) occurred in the cellular fraction of the saliva, in comparison to sham treated control, without significant accompanying changes in TSPO Bmax , TSPO protein levels, or general protein levels. The changes in affinity of TSPO from the cellular fraction of saliva exposed to cigarette smoke were accompanied by changes in the mean levels of protein oxidation products (carbonyls) and lipid peroxides, which were three-fold higher (p < 0.01) and two-fold higher (p < 0.01), respectively, compared to those of sham treated controls. Thus, our study shows that TSPO is present in the cellular component of saliva. Interestingly, in vitro this cellular TSPO is affected by exposure of the whole saliva to cigarette smoke, in negative correlation with oxidative stress.

Lycopene, a natural carotenoid found in tomato, has been reported to possess various health benefits, such as cardiovascular and cancer preventive properties. However, the experimental basis for such health benefits is not fully understood. One of the possible mechanisms for its protective activities is by down-regulation of the inflammatory response. That includes the inhibition of pivotal pro-inflammatory mediators, such as the reduction of reactive oxygen species, the inhibition of synthesis and release of pro-inflammatory cytokines, changes in the expression of cyclooxygenase and lipoxygenase, modifications of eicosanoid synthesis, and modulation of signal transduction pathways, including that of the inducible nitric oxide synthase via its inhibitory effects on Nuclear Factor-kB (NF-kB), Activated protein-1 (AP-1) and mitogen-activated protein kinase (MAPK) signaling. Recent data suggest that lycopene also exhibits anti-inflammatory activity through induction of programmed cell death in activated immune cells. This review will discuss recent data on the control of inflammatory signaling exerted by tomato lycopene in isolated cells, in animal models and in clinical trials, focusing on the dose of the carotenoid and the biological environment in which it acts. A clear understanding of the molecular mechanisms of action of lycopene is crucial in the valuation of this molecule as a potential preventive and therapeutic agent.