Current Medicinal Chemistry - Volume 14, Issue 3, 2007

Homocysteine is a thiol aminoacid synthesized during the metabolism of methionine. Increased plasma levels of homocysteine can be the result of mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine-β synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR). Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or vitamin B12 (methylcobalamin), can induce hyperhomocysteinemia. Over the last decade, following in vitro and in vivo observations of a homocysteine-associated vascular pathology, convincing epidemiological evidence has been gathered on the relation between moderate elevation of plasma homocysteine and vascular disease, including cerebral ischemia. However, causality has yet to be established. The association between homocysteine and ischemic stroke might be a spurious epidemiological finding because of confounding or it might reflect reverse causality. If this is the case, elevated levels of plasma homocysteine should be interpreted as an epiphenomenon secondary to the vascular disease itself. Thus, whether lowering homocysteine concentration prevents cerebral ischemia remains to be determined. The only method to answer the question of the causal relation between homocysteine and ischemic stroke is by intervention trials in which patients at high vascular risk, such as those who have had a recent cerebral ischemic event are randomly allocated to placebo or homocysteine-lowering multivitamin therapy, and followed prospectively. Some of these randomized controlled trials are currently ongoing. Their results should hopefully resolve the issue in the next future.

Recently interest has been focused on the administration of allergen specific immunotherapy by the oral route particularly sublingually. The mechanism by which sublingual immunotherapy exerts its effects remain unclear. Most likely, allergen captured within the oral mucosa by Langerhan's-like dendritic cells play a role in subsequent T cell responses. There is a growing body of evidence to support the role of regulatory T cells in controlling the development of allergic diseases. Nevertheless, there remains a lack of firm evidence that sublingual immunotherapy induces regulatory T cells. New vaccine developments with the increasing understanding of the molecular engineering techniques are on the way to offer the opportunity to design recombinant allergens that are safe, effective and easy to administer. In addition, the idea of using adjuvants along with allergen within the oral cavity is another promising approach.

Annexins are characterized by the ability to bind phospholipids of membranes in the presence of Ca2+. Annexin A5 represents a typical member of this protein family and is a natural occurring highly specific ligand for phosphatidylserine (PS). The exposure of PS is one major “eat me” signal for phagocytes of apoptotic and necrotic cells. Apoptotic cells are normally cleared via an anti-inflammatory pathway. In contrast, the uptake and removal of necrotic cells normally involves inflammation and an immune response. Interestingly, the lack of endogenous annexin A5 also leads to a reduced inflammatory potential of necrotic cells. Annexin A5 may interfere in vivo with the immunosuppressive effects of apoptotic cells since it preferentially binds PS with high affinity and inhibits apoptotic cell uptake by macrophages. In this review we focus on how defects in the clearance process can lead to chronic autoimmunity. Furthermore, the role of annexin A5 as important adjuvant for apoptotic cell-based tumour vaccines is discussed. The mechanism of how the immunogenicity of apoptotic cells can be restored by blocking their PS-dependent clearance is outlined in detail. Taken together, annexin A5 is an important modulator of the immune response against PSexposing particles like apoptotic cells, necrotic cells, and certain viruses.

Cardiovascular diseases as hypertension, angina and/or supraventricular arrhythmias are among the most important death causes in the world. For the treatment of heart pathologies, calcium channel entry blockers are very important drugs, owing to their therapeutic versatility. Although few calcium antagonists described until today are structurally related to diltiazem and to the benzothiazepine class, the still high pharmaceutical interest on diltiazem analogues justifies this review. Diltiazem and its first analogues developed in the early '70s became popular in the '80s, and were pharmacologically characterized for a long time. It is in the '90s that several research groups carried out structural variations identifying novel scaffolds for diltiazem-related compounds, with significant calcium antagonist behaviour. Recently, a series of thiazino-oxadiazolone derivatives were identified as potent and selective antagonists for calcium influx into cardiac cells, and they were subsequently used to search for novel chemotypes by means of virtual screening techniques. The resulting hits could open interesting perspectives for the development of drugs to treat cardiovascular diseases. In the present review, an updated collection of diltiazem analogues is reported over the last ten years. The chemical structure and the structure activity relationships will be given, with additional mention to the potential therapeutic applications.

Malaria is the most important parasitic disease worldwide, affecting more than 500 million people and causing close to 1 million deaths per annum. This serious fact is mainly attributable to the emergence of drug resistant strains of Plasmodium falciparum. The advances made in malaria chemotherapy based on unique aspects of the biochemistry and physiology of the responsible agents for this disease, parasites of Plasmodium genus, are covered in this review. Increasing resistance to conventional antimalarial drugs constitutes the main drawback for the persistence of this disease. In the present article, a comprehensive analysis of selected molecular targets is depicted in terms of their potential utility as chemotherapeutic agents. Our review focuses on different and important molecular targets for drug design that include proteases that hydrolyze hemoglobin, protein farnesyltransferase, heme detoxification pathway, polyamine pathways, dihydrofolate reductase, artemisinin-based combination therapies (ACTs), etc. Therefore, rational approaches to control malaria targeting metabolic pathways of malaria parasites which are essential for parasites survival are presented.

This review critically surveys the literature published mainly within this millennium on the new and emerging applications of silybin (pure, chemically defined substance) and silymarin (flavonoid complex from Silybum marianum - milk thistle seeds). These compounds used so far mostly as hepatoprotectants were shown to have other interesting activities, e.g. anticancer and canceroprotective and also hypocholesterolemic activity. These effects were demonstrated in a large variety of illnesses of different organs, e.g. prostate, lungs, CNS, kidneys, pancreas and also in the skin protection. Besides the cytoprotective activity of silybin mediated by its antioxidative and radical-scavenging properties also new functions based on the specific receptor interaction were discovered. These were studied on the molecular level and modulation of various cell-signaling pathways with silybin was disclosed - e.g. NF-κ B, inhibition of EGFR-MAPK/ERK1/2 signaling, activity upon Rb and E2F proteins, IGF-receptor signaling. Proapoptotic activity of silybin in pre- and/or cancerogenic cells and anti-angiogenic activity of silybin are other important findings that bring silymarin preparations closer to respective application in the cancer treatment. Discovery of the inhibition and modulation of drug transporters, Pglycoproteins, estrogenic receptors, nuclear receptors by silybin and some of its new derivatives contribute further to the better understanding of silybin activity on the molecular level. Silymarin application in veterinary medicine is reviewed as well. Recent works using optically pure silybin diastereomers clearly indicate extreme importance of the use of optically active silybin namely in the receptor studies. Significance of silymarin and its components in the medicine is clearly indicated by an exponential growth of publications on this topic - over 800 papers in the last 5 years.

Loads of reactive oxygen species (ROS), including superoxide anion and nitric oxide, that overburden antioxidant systems induce oxidative stress in the body. Major cellular targets of ROS are membrane lipids, proteins, nucleic acids, and carbohydrates. Circumstantial evidence suggests that ROS play a crucial role in the initiation and progression of various diseases in children and adolescents. The involvement of ROS and oxidative stress in pediatric diseases is an important concern, but oxidative stress status in young subjects and appropriate methods for its measurement remain to be defined. Recently, specific biomarkers for oxidative damage and antioxidant defense have been introduced into the field of pediatric medicine. This review is intended to provide an overview of clinical applications of oxidative stress biomarkers in the field of pediatric medicine. First, this review presents the biochemistry and pathophysiology of ROS and antioxidant defense systems. Second, it presents a list of clinically applicable biomarkers, along with pediatric diseases in which enhanced oxidative stress might be involved. The discussion emphasizes that several reliable biomarkers are easily measurable using enzyme-linked immunosorbent assay. Third, this review presents agerelated reference normal ranges of oxidative stress biomarkers, including urinary acrolein-lysine, 8-hydroxy- 2'-deoxyguanosine, nitrite/nitrate, and pentosidine, and the changes of the parameters in several clinical conditions, including atopic dermatitis and diabetes mellitus. New and interesting data on oxidative stress and antioxidant defenses in neonatal biology are also presented. Fourth, this review discusses the everaccumulating body of data linking oxidative stress to disturbances of the nitric oxide system and vascular endothelial activation/dysfunction. Finally, this review describes the reported clinical trials that have evaluated the efficacy of antioxidants for oxidative-stress related diseases. Suggestions are advanced for the direction of future trials using antioxidant therapies. Repeated measurement of appropriate parameters will enable us to discern the pathophysiological patterns of pediatric diseases and guide our therapies appropriately.

Premature ovarian failure (POF) is defined as the cessation of ovarian function under the age of 40 years and is characterized by amenorrhea, hypoestrogenism, and elevated serum gonadotropin concentrations. POF affects 1% of all women and occurs in approximately 0.1% before the age of 30 years. To date, mutations associated with POF have been identified in a small number of genes, including those encoding inhibinα (INHA), the FSH receptor and the LH/chorio gonadotrophin receptor. Germ cell specific genes such as Gdf9, Bmp15, and Rfpl4 may also play important roles in human oogenesis. Transcription factors that regulate oocyte gene expression in animal models and include Nobox, Taf4b, Figla, Lhx8, Sohlh1 and Sohlh2 are likely to be key mediators of fertility in humans. In this review, after summarizing the general background on human POF, we focus on insights gained from the animal models with regards to mammalian folliculogenesis. Studies in animal models provide new candidate genes for ovarian failure in humans.

Psoriatic arthritis (PsA), an inflammatory joint disease associated with psoriasis of the skin, has a heterogeneous pattern expressed by different manifestations, such as mild mono-oligoarthritis, a very severe, erosive and destructive polyarthritis indistinguishable from rheumatoid arthritis, and spondylarthropathy with axial involvement or enthesitis. The disease pattern often differs between patients as well as within the same patient over time. Measurable inflammatory activity is not always evident. Early detection of inflamed joints or axial involvement in patients with PsA is important in order to reduce the inflammation and prevent destruction, deformity and functional disability in the joints involved. Several factors, e.g., genetic, immunological, environmental and vascular, have been proposed to be of importance for the aetiology, the expression and prognosis of PsA. The basic treatment for PsA has been administration of non-steroid anti-inflammatory drugs (NSAIDs). Few disease modifying anti-rheumatic drugs (DMARDs) have been available due to a lack of efficacy of most of the DMARDs used for other rheumatic diseases. New insights into genetic, immunological and vascular factors in PsA are of interest as possible targets for future therapy and will be discussed in this review.

The NF-κB/Rel signaling system is a paradigm for gene activation in response to inflammatory and menacing stimuli. Given the growing body of evidence showing an important involvement of NF-κB for the onset of autoimmune diseases and different types of cancer, NF-κB is an important drug target for the adjuvant therapy of these diseases. Great efforts have been made for the development of highly specific NF-κB inhibitors, some of them being currently tested in phase II clinical trials. Here we discuss recent progress in the identification of druggable components of the NF- κB signaling system and the development and potential use of novel NF-κB inhibitors.