Current Medicinal Chemistry - Volume 14, Issue 15, 2007

Cyclooxygenase (COX) is the rate limiting enzyme catalyzing the conversion of arachidonic acid into prostanoids, lipid mediators critically implicated in a variety of physiological and pathophysiological processes, including inflammation, vascular and renal homeostasis, and immune responses. Since the early 1990s it has been appreciated that two isoforms of COX exist, referred to as COX-1 and COX-2. Although structurally homologous, COX-1 and COX-2 are regulated by two independent and quite different systems and have different functional roles. In the setting of acute ischemic syndromes it has been recognized that COX pathway plays an important role; however, whereas the function of platelet COX-1 in acute ischemic diseases is firmly established, the role of COX-2 in atherothrombosis remains controversial. The complex role of COX-2 in this setting is also confirmed by the unexpected cardiovascular side effects of long-term treatment with COX-2 inhibitors. In this article, we review the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque vulnerability, the effects of the variable expression of upstream and downstream enzymes in the prostanoid biosynthesis on COX-2 expression and inhibition.

Asthma is characterized by airway inflammation, bronchial hyper-responsiveness, and reversible airway obstruction. Medications for asthma include corticosteroids, β2-adrenergic receptor agonists, chromones, methylxanthines, and leukotriene modifiers. Despite these advances in therapy, many symptoms are not well controlled. Since asthma is a chronic airway inflammation with a bias towards a type 2 T helper (Th2) cell response, some new approaches are targeted towards the Th2 inflammation pathway. These include anti-IgE therapy, anti-Th2 cytokine therapy, and therapies aiming at increasing Th1 cytokines. This article will focus on DNA-based therapy, a novel therapeutic strategy for asthma. Immunostimulatory gene therapy using CpG oligodeoxynucleotides with central deoxycytidyl-deoxyguanosine (CpG) dinucleotide, in which the cytosine nucleobase is unmethylated, can stimulate the innate immunity and augment Th1 response. With DNA gene therapy, genes can be introduced to target Th1 cytokines or other mediators in the airway in order to counteract Th2 inflammation in asthma. Also, antisense oligonucleotides can target mRNA species of interest in asthma. Through these therapies, we can expect long-lasting effects, better control of symptoms, and reducing medication in the future.

Cardioprotective interventions are defined as interventions able to increase myocardial resistance to ischemia. The authors approach the issue of cardioprotection on the basis of the present knowledge about the biochemical mechanisms responsible for the injury produced by myocardial ischemia or ischemia-reperfusion. Reversible and irreversible injury are distinguished. The former is largely accounted for by the direct consequences of reduced ATP synthesis, which causes decreased ATP phosphorylation potential, acidosis and phosphate accumulation. The biochemical mechanisms leading to irreversible injury include osmotic overload, production of toxic lipid metabolites, cytosolic calcium overload, and generation of reactive oxygen species, which lead to membrane disruption, mitochondrial dysfunction and possibly to the activation of apoptotic pathways. The major effect of the classical cardioprotective agents (nitrates, beta adrenergic antagonists, calcium channel blockers) consists in affecting ATP demand/supply ratio in such a way as to delay the decrease in ATP phosphorylation potential. Other drugs have been introduced, which allegedly interfere directly with the mechanisms responsible for irreversible ischemic injury. These include 3-ketoacyl-CoA tiolase inhibitors, modulators of intracellular calcium channels, ionic exchanger inhibitors, free radical scavengers, caspase inhibitors, purinergic agonists, K+ ATP channel openers, and modulators of mitochondrial permeability transition. The results obtained with these substances in experimental models and in the clinical setting are discussed. Special attention is devoted to angiotensin converting enzyme inhibitors, whose direct cardioprotective properties has recently been demonstrated.

A challenging question in biology is how cells control their shape and volume. The relative abundance of organelles can be radically modified to comply with a new task, an example being the massive development of the endoplasmic reticulum (ER) in Ig-secreting plasma cells. The ER is the site where secretory proteins are made and folded. Remarkably, it can discriminate between native and non-native proteins, restricting transport to the former, whilst retaining and eventually degrading the latter (quality control). Recent studies revealed that certain components of the unfolded protein response (UPR), a multidimensional signalling pathway originally discovered in cells exposed to severe ER stress, are crucial for the normal development of secretory cells. According to the cell types, different arms of the UPR are required: the IRE1-XBP1 pathway is essential for plasma cell differentiation, whilst the PERK-eIF2α pathway is essential for pancreatic β cells survival. Therefore, the UPR is far from being a monolithic response. Disturbances in the signalling pathways that allow the ER to satisfy the changing demand of protein synthesis can occur at various levels and often cause diseases. Here we summarize the molecular mechanisms underlying this variegated and constantly growing class of pathological conditions, focusing on diseases that are linked to alterations in the quality control functions that the ER exerts over its protein products.

Protein glycation is a slow natural process involving the chemical modification of the reactive amino and guanidine functions in amino acids by sugars and carbohydrates-derived reactive carbonyls. Its deleterious consequences are obvious in the case of long-lived proteins in aged people and are exacerbated by the high blood concentration of sugars in diabetic patients. The non-enzymatic glycation of proteins occurs through a wide range of concurrent processes comprising condensation, rearrangement, fragmentation, and oxidation reactions. Using a few well established intermediates such as Schiff base, Amadori product and reactive a-dicarbonyls as milestones and the results of in vitro glycation investigations, an overall detailed mechanistic analysis of protein glycation is presented for the first time. The pathways leading to several advanced glycation end products (AGEs) such as (carboxymethyl)lysine, pentosidine, and glucosepane are outlined, whereas other AGEs useful as potential biomarkers of glycation are only briefly mentioned. The current stage of the development of glycation inhibitors has been reviewed with an emphasis on their mechanism of action.

Photodynamic therapy (PDT) is a relatively new cytotoxic treatment, predominantly used in anticancer approaches, that depends on the retention of photosensitizers in tumor and their activation after light exposure. This technology is based on the light excitation of a photosensitizer which induces very localized oxidative damages within the cells by formation of highly reactive oxygen species, the most important being singlet oxygen. Many photo-activable molecules have been synthesized such as porphyrins, chlorins and more recently phthalocyanines which present a strong light absorption at wavelengths around 670 nm and are therefore well-adapted to the optical window required for PDT application. However, the lack of selective accumulation of these photo-activable molecules within tumor tissue is a major problem in PDT, and one research area of importance is developing targeted photosensitizers. Indeed, targeted photodynamic therapy offers the advantage to enhance photodynamic efficiency by directly targeting diseased cells or tissues. Many attempts have been made to either increase the uptake of the dye by the target cells and tissues or to improve subcellular localization so as to deliver the dye to photosensitive sites within the cells. The aim of this review is to present the actual state of the development of phthalocyanines covalently conjugated with biomolecules that possess a marked selectivity towards cancer cells; for some of them their photophysical properties and photodynamic activity will be presented.

Adrenomedullin (AM) is a potent vasodilatory peptide originally discovered in human pheochromocytoma tissue. AM and AM gene expression are widely distributed in the cardiovascular system, including the kidney. The co-localization of AM and its receptor components such as calcitonin receptor-like receptor (CRLR), receptor activity modifying protein (RAMP)2 and RAMP3 in the kidney, heart, and vasculature suggests an important role for the peptide as a regulator of renal, cardiac, and vascular function. Indeed, in addition to its cardiovascular effects, AM has renal vasodilatory, natriuretic, and diuretic actions. Consistent with these observations, immunohistochemical studies revealed that AM is stained in the collecting duct, distal convoluted tubules, vessels, and glomerular mesangial cells, endothelial cells and podocytes. Plasma AM levels are increased in patients with renal impairment in proportion to the severity of the disease. Previously we and other investigators showed that two molecular forms of AM, AM-glycine, an inactive form, and AM-mature, an active form, circulate in human plasma. Urine also contains both forms of AM; however, the AM-mature/AM-glycine ratio is higher in urine than in plasma. Interestingly, plasma AM-glycine and AM-mature levels are increased in renal failure, whereas urinary AM-glycine and AM-mature are decreased in this condition. These results indicate that the origin of urinary AM is different from that of plasma AM. Experimental studies showed that the renal tissue AM-mature/AM-glycine ratio is higher than that in plasma and urine. In addition, renal tissue concentrations of AM are increased in severely hypertensive rats. Considering that AM has antiapoptotic, antifibrotic, and antiproliferative effects, the increase of AM in renal disease may be a protective mechanism. In fact, AM gene delivery or longterm AM infusion significantly improved glomerular sclerosis, interstitial fibrosis, and renal arteriosclerosis in several malignant hypertensive models. This review describes the biochemistry, physiology, and circulating levels of AM and also discusses what is known about the pathophysiological role of AM in renal disease.

In our review entitled “Radioligand Development for PET Imaging of -Amyloid (Aβ) ” Current Status” by Cai, et al. in Current Medicinal Chemistry, 2007, 14 , 19-52. Please note brain uptake values at 2, 30, and 60 min in Table 23 are not uniformly in %SUV [(%ID/g) x g (body weight)] as implied. For example, the data shown are [(%ID/g) x kg (body weight)] for PIB in mouse and %ID/g for IMPY also in mouse. Because the average mouse weighs about 30 g (0.03 kg), the value for IMPY would need to be corrected by a factor of about 0.03 to be directly comparable with that of PIB. A compound with a brain uptake of 0.21 %ID/g at 2 min would not be the same as PIB. In fact, that compound would be about 30-fold inferior to PIB with regard to brain uptake and would likely fail as an in vivo imaging agent. The numbers are taken directly from the original references. Due to lack of animal body weight data and the different species from which data had been obtained, strictly comparable SUV values could not be calculated. However, these differences were mistakenly not noted in the Table. Interested readers should consult the original references for details. The ratios of radioactivity between 2 and 30 min, or 2 and 60 min, as listed in the Table remain correct. We apologize for this error and the inconvenience to the reader.