Current Medicinal Chemistry - Volume 14, Issue 16, 2007

Oxidative reactions caused by cigarette smoke (CS) chemicals have been shown to initiate crucial events in atherogenesis. However, physicians and scientists are confronted with the paradoxical situation that an antioxidative treatment of smokers improves acute smoking effects but hardly has any impact on long term outcome of cardiovascular diseases (CVD). In this review we make an attempt to explain this paradox. First, smoke-derived free radicals and oxidants are part of CS causing a pro-oxidative state in the circulatory system. Further, smoke chemicals down-regulate antioxidant defence enzymes that would counteract the oxidative burden by cigarette smoke. With the prolonged exposure to smoke, oxidation catalysing metals accumulate in the vessel wall and mediate local oxidation reactions. Therefore, pharmacological intervention relying on nonselective antioxidants often appears to be ineffective. Consequently a novel strategy for the prevention and treatment of CVD caused by smoking is suggest, relying on a combined application of antioxidants, substitution of factors important for physiological oxidant defence, and metal-detoxifying agents.

The objective of this article is to illustrate both the potential and the limitations of molecular imaging in stroke research. By molecular imaging we mean the visual representation of biological processes at the cellular and molecular level. The use of molecular imaging for stroke diagnosis is still at a very preliminary stage and many of these procedures have only been tested in animals. In rats, stroke therapy using stem cells can be monitored by magnetic resonance imaging (MRI), green fluorescent protein (GFP) or luciferase (LUC) imaging. The migration of macrophages, which take up intravenously administered iron-based contrast agents and then migrate to the area of infarction, can already be observed in stroke patients. With MRI, the new agent Gd-DTPA-sLexA that binds to E- and Pselectin can specifically visualize selectin-mediated early endothelial activation after transient focal ischemia “in vivo”. Decreased glial fibrillary acidic protein (GFAP) gene expression can be imaged in vivo by scintigraphy 24 hours after cerebral ischemia using a peptide nucleic acid antisense conjugate labeled with 111In and that hybridizes to the rat GFAP mRNA. Technetium-99m hydrazine nicotinamide- labeled HYNIC-annexin V SPECT can not only detect sites of neuronal injury in stroke patients but also can monitor the effects of neuroprotective therapy with a monoclonal antibody raised against FasLigand (FasL) in rats. Finally, information about cell metabolism in the infarct region can be gained using certain intracellular tracers [e.g. 18F-fluoromisonidazole (FMISO)]. Imaging benzodiazepine receptors with 11C-flumazenil (FMZ) can distinguish between irreversibly damaged and viable penumbra tissue early after stroke.

Diabetes mellitus (DM) is a significant healthcare concern worldwide that affects more than 165 million individuals leading to cardiovascular disease, nephropathy, retinopathy, and widespread disease of both the peripheral and central nervous systems. The incidence of undiagnosed diabetes, impaired glucose tolerance, and impaired fasting glucose levels raises future concerns in regards to the financial and patient care resources that will be necessary to care for patients with DM. Interestingly, disease of the nervous system can become one of the most debilitating complications and affect sensitive cognitive regions of the brain, such as the hippocampus that modulates memory function, resulting in significant functional impairment and dementia. Oxidative stress forms the foundation for the induction of multiple cellular pathways that can ultimately lead to both the onset and subsequent complications of DM. In particular, novel pathways that involve metabotropic receptor signaling, protein-tyrosine phosphatases, Wnt proteins, Akt, GSK-3β, and forkhead transcription factors may be responsible for the onset and progression of complications form DM. Further knowledge acquired in understanding the complexity of DM and its ability to impair cellular systems throughout the body will foster new strategies for the treatment of DM and its complications.

A small group of patients affected by type 1 diabetes mellitus is characterized by a severe instability of glycemic values with frequent and unpredictable hypoglycemic and/or ketoacidosis episodes which cannot be explained by errors of patients or diabetologists. The quality of life of these patients is dramatically compromised in particular because of the frequency of acute events, hospital recoveries and precocious appearance of chronic complications. This clinical condition has been defined as “brittle diabetes”. A precise quantification of these patients is difficult because diagnostic criteria are still not well defined and it is often difficult to verify errors of patients in terms of inappropriate conduct with the pathology. Even more than the other kinds of diabetes, therapy is based on education, glycemic control, intensive therapy and strict interaction between physicians and patients. The introduction of insulin analogous, with either ultra-fast and ultra-slow action and the use of subcutaneous insulin pumps have significantly increased the possibility of treating the most of these cases. However, there is a minority of patients resistant to the therapy. In similar cases, pancreas or islet transplantation represents an effective therapeutic option entailing good expected outcomes. The main limiting factor of beta cell function replacement by transplantation is so far represented by the potentially severe side effects of the immunosuppression therapy necessary to avoid graft rejection and recurrence of autoimmunity.

Pancreatic and duodenal homeobox factor-1 (PDX-1) plays a crucial role in pancreas development, β-cell differentiation, and maintaining mature β-cell function. At an early stage of embryonic development, PDX-1 is initially expressed in the gut region when the foregut endoderm becomes committed to common pancreatic precursor cells. During pancreas development, PDX-1 expression is maintained in precursor cells, and later it becomes restricted to β-cells. In mature β-cells, PDX-1 transactivates the insulin gene and other genes involved in glucose sensing and metabolism, such as GLUT2 and glucokinase. MafA is a recently isolated β-cell-specific transcription factor which functions as a potent activator of insulin gene transcription. During pancreas development, MafA expression is first detected at the beginning of the principal phase of insulinproducing cell production. Furthermore, these transcription factors play a crucial role in inducing surrogate β-cells from non-β- cells and thus could be therapeutic targets for diabetes.

Changes of extracellular pH values can have profound effects on neuronal function. For example, the low pH (also called acidosis) generated in brain ischemia causes acute neuronal injury. For years the receptors that detect pH variations surrounding neurons and their physiological/pathological importance remain uncertain. The recent finding that acidosis activates a distinct family of membrane ion channels, the acid-sensing ion channels (ASICs) in both peripheral and central neurons has dramatically changed the view of acidosis-associated signaling and provided a new strategy for therapeutic inventions. Although proton is the only known agonist for the activation of ASICs, a variety of extracellular and intracellular signaling molecules can modulate the activities of ASICs and have profound influence on the functions of these channels in both physiological and pathological processes. The goal of this article is therefore to provide a comprehensive review of the modulators of ASICs that adapt ASIC activity to changes of extracellular and intracellular environments.

Erectile dysfunction (ED) is a common condition with a significant effect on quality of life. The prevalence of ED increases with age and other risk factors (hypertension, diabetes, smoking, coronary heart disease, dyslipidemia and depression). Nitric oxide (NO) activity is adversely affected, in penile and vascular tissue, by these risk factors. Endothelial dysfunction and a reduced generation or bioavailability of NO have emerged as major pathophysiological mechanisms in ED. Hyperlipidemia may impair erectile function by affecting endothelial and smooth muscle cells of the penis. Oxidized low-density lipoprotein is a causative factor for the impaired relaxation response of the corpus cavernosum. Elevated serum cholesterol and reduced high density lipoprotein cholesterol levels are associated with an increased risk of ED. It follows that treating dyslipidemia could have a beneficial effect on ED. Phosphodiesterase type 5 inhibitors are now considered as first line treatment for ED. There is evidence that statins improve responses to these drugs. ED is considered as a warning sign of silent or early vascular disease. The use of statins may be beneficial in these patients.

Exposure of the human population to chlorination products has considerably increased during the 20th century especially after the 1960s with the development of public and leisure pools. The present article summarizes current knowledge regarding the human exposure to chlorination products and reviews studies suggesting that these chemicals might be involved in the development or exacerbation of allergic diseases. Populations regularly in contact with chlorination products such as swimmers, lifeguards or workers using chlorine as cleaning or bleaching agent show increased risks of allergic diseases or of respiratory disorders frequently associated with allergy. Experimental evidence suggests that chlorination products promote allergic sensitization by compromising the permeability or the immunoregulatory function of epithelial barriers. These findings led to the chlorine hypothesis proposing that the rise of allergic diseases could result less from the declining exposure to microbial agents (the hygiene hypothesis) than from the increasing and largely uncontrolled exposure to products of chlorination, the most widely used method to achieve hygiene in the developed world. Giving the increasing popularity of water recreational areas, there is an obvious need to assess the effects of chlorine-based oxidants on human health and their possible implication in the epidemic of allergic diseases.

Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the nervous system. It is estimated that 75-150 million people in the United States have a chronic pain disorder. Neuropathic pain has a great impact on the quality of life. It is debilitating and often has an associated degree of depression that contributes to decreasing human wellbeing. Moreover, the management of chronic pain is costly to the health care system. The United States Congress has declared the present decade (2001-2010) as the “Decade of Pain Control and Research”, making pain a national healthcare priority. In Europe, statistics provided by the International Association on the Study of Pain (IASP) and the European Federation of the IASP Chapters (EFIC) indicate that one in five people suffer from moderate to severe chronic pain, and that one in three are unable or less able to maintain an independent lifestyle due to their pain. Between one-half and two-thirds of people with chronic pain are less able or unable to exercise, enjoy normal sleep, perform household chores, attend social activities, drive a car, walk or have sexual relations. The effect of pain means that one in four reports that relationships with family and friends are strained or broken, according to the IASP/EFIC data. Neuropathic pain treatment is extremely difficult. Neuropathic pain is a very complex disease, involving several molecular pathways. Excitatory or inhibitory pathways controlling neuropathic pain development show altered gene expression, caused by peripheral nerve injury. Current available drugs are usually not acting on the several mechanisms underlying the generation and propagation of pain. Nowadays, pain research is directing on new molecular methods, such as gene therapy, stem cell therapy and viral vectors for delivery of biologic antinociceptive molecules. These methods could provide a new therapeutic approach to neuropathic pain relief.

The marine organisms are a rich source of varied natural products with unique functionality. Marine natural products chemistry has undergone an explosive growth during the past three decades. A variety of natural products of new molecular structures with diverse biological activities have been reported from marine flora and fauna, thus ensuring motivation in the search of newer natural products. The bis and trisindole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads. 3-hydroxy staurosporine 51, an indolo carbazole having powerful antiproliferative activity. Hamacanthin A 1 and B 2, pyrazinone alkaloids have significant antimicrobial activity. Coscinamides 60-62 and Chondriamides 63-65 an indolic enamides which have anti-HIV and cytotoxic activity respectively. Gelluisine A 66 and B 67, trisindole alkaloids have strong anti-serotonin activity and strong affinity with somatostatin and neuropeptide Y receptors in receptor-binding assays. This report reviews the literature on these alkaloids of marine origin and highlights the isolation, structure, latest synthesis and specific biological activities including cytotoxicity, antiviral, antiparasitic, serotonin antagonism and other pharmacological activities of sixty-nine bis and trisindole alkaloids.

The figure on the cover was published in Curr. Med. Chem., Volume 13, Number 2, 2006. On the next page of this issue, Osman Guner and Omoshile Clement, from Accelrys, 9685 Scranton Road, San Diego, CA 92121, USA, and Yasuhisa Kurogi, from Cambridge Isotope Laboratories, Inc., 50 Frontage Road, Andover, MA 01810, USA, fraudulently assigned to themselves the authorship of this figure. However, the real authors are Albert Palomer, Francesc Cabre, Jaume Pascual, Lluisa Garcia, and David Mauleon, from the R & D Department, Laboratorios Menarini S. A., Alfonso XII 587, 08918 Badalona, Spain, and Joaquin Campos, Maria A. Trujillo, Antonio Entrena, Miguel A. Gallo, and Antonio Espinosa, from the Departamento de Quimica Organica, Facultad de Farmacia, Universidad de Granada, Campus de Cartuja s/n, 18071 Granada, Spain. The cover slide shows the catalyst-generated pharmacophore model for the COX-2 inhibition aligned with the proteinbound structure of SC-558 (green), and a novel computer-designed COX-2 lead (red). The figure is reprinted with permission from the J. Med. Chem., 2002, 45, 1402-1411. Copyright (2007) American Chemical Society.