Current Medicinal Chemistry - Volume 20, Issue 6, 2013

Ischemic insults and neurodegenerative diseases are by far the leading cause of mortality and disability. Whole-body hypoperfusion, as it occurs in polytraumatic and hemorrhagic shock, is alike an increasingly frequent condition, especially due to traffic accidents, wars and acts of terrorism. It is now clearly established that inflammatory processes play a fundamental role in the pathophysiology of both hypoperfusion/ischemia damage (be it generalized to the whole body, as in the case of shock, or limited to individual organs) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis). On the other hand, concurrent animal and human data show that melanocortin peptides with agonist activity at melanocortin MC3/MC4 receptors are highly effective in different shock conditions as well as in conditions of ischemia/ischemia-reperfusion of individual organs (heart, brain, intestine, kidney, etc.), and accumulating evidence indicates that such effects of melanocortins are mostly due to quite peculiar antiinflammatory mechanisms. Melanocortins have also long been known (i) to exert important neurotrophic effects, not only during fetal development but also in adulthood, in different animal models of brain lesions; (ii) to reduce the morphological correlates of brain aging; (iii) to retard the behavioral deficits that develop during the aging process. Moreover, recent data from different laboratories show that after brain ischemic episodes melanocortins activate the transcription of neurotrophins and their receptors in the cerebral cortex and in the hippocampus, and increase the proliferation of progenitor neuron cells. The above arguments support the view that pharmacokinetically suitable agonists at MC3/MC4 melanocortin receptors may represent a completely innovative class of drugs for an effective treatment of both ischemic and neurodegenerative diseases.

In spite of the unquestionable positive impact of HAART in the treatment of HIV infection, the discovery and development of novel agents directed towards other targets of the replicative cycle of the virus that differ from those targeted by the clinically approved drugs, emerges nowadays as an imperative need. The blockade of HIV entry is a highly promising strategy against the pathogen and glycoprotein gp120 is a central actor in this process. This review discusses the current status in the research of anti-HIV agents targeting specifically the envelope protein gp120. The diverse approaches devoted to the achievement of therapeutic agents against gp120 currently under study are organized and analyzed critically according to their specific mechanism of inhibition and structural features.

In recent years, there has been escalating interest in the biomedical applications of nanoparticles (NPs). In particular, silver nanoparticles (AgNPs) are increasingly being investigated as tools for novel cancer therapeutics, capitalizing on their unique properties to enhance potential therapeutic efficacy. However, questions as to are we able to contain or control the toxicity effects of AgNPs, and how much do we know about the toxicological profile of AgNPs which are commonly used in emerging nanotechnology-based applications, still remain. Hence, serious considerations have to be given to the hazards and risks of toxicity associated with the use of AgNPs. This review focuses on the current applications of AgNPs, their known effects and toxicity, as well as the potential of harnessing them for use in cancer therapy.

This review summarized the progress of glyconanoparticles in the aspects of types, synthesis, and applications for recent five years. A major challenge in the development of Au glyconanoparticles for the study of cellular interactions is to span the cellular membrane, which is used for the drug delivery. A majority of glyco-functionalized quantum dots have been utilized as fluorescent probes for biolabeling, imaging and biosensing. Recently, magnetic nanoparticles have been more frequently used in biomedical applications. The application of these new multivalent systems of glyconanoparticles is to mainly study carbohydrate-mediated interactions, which opens the new field in glycobiology.

Elemental analysis can be applied in the medical field to investigate the causes of disease. In patients with some pulmonary diseases, elements can be found in the exogenous dust deposited in the lungs and are also accumulated through the loss of cell homeostasis. Diseases induced by inhalation of dust typically affect the lungs. Although there are many pulmonary diseases induced by dust inhalation, it is often difficult to clarify the exact cause. In-air microparticle induced X-ray emission (in-air micro-PIXE) analysis is a method of elemental analysis that employs a proton ion-beam to directly measure the content of elements and their distribution in frozen sections or paraffin sections of tissue. We constantly inhale particles while breathing, but most of us do not develop pulmonary disease. Because in-air micro-PIXE analysis can determine the two-dimensional localization and content of particles in tissue, we can clarify the relationship between inhaled particles and diseases based on such analysis and the immunohistochemical expression of disease-related proteins. Elemental analysis methods like in-air micro-PIXE analysis may be useful for making precise diagnosis amd assesing disease progression to overcome threat such as occupational or environmental exposure.

the present review focuses on the synthesis and biological evaluation of polycyclic 4(3H)-quinazolinones containing fused aromatic or heteroaromatic rings. The first part of the review is related to compounds with ring fused to the pyrimidine part of the quinazoline core. Most of the quinazolinone alkaloids belong to this class of molecules. The second part presents molecules bearing extra ring(s) fused to the benzo moiety of the quinazolinone skeleton. Their structural diversity opens new fields in the search of active molecules.

The term multivalency (polyvalency) in the biological science is defined as the simultaneous binding of multiple ligands to one receptor (or multiple receptors to one ligand). The possibility of gaining potency and selectivity was significantly increased through the use of multivalent ligand as a homo- or hetero-dimer, thus multivalent ligands provided a more attractive strategy to design novel anti-HIV agents with therapeutic applications. Moreover, similar to phenomenon of multivalency, an alternative strategy is called the “mixed sites inhibitor”, viz. a single molecule that possesses enough chemical space to maximize interactions with its complementary binding pocket, or to bind simultaneously in more than one regions in a target. Actually, the addition of a third heterocyclic nucleus to the parent compound resulted in “mixed sites” anti-HIV agents with broad spectrum of activities against the mutant HIV-1 strains. Based on current representative examples, the present article provided a brief review on the rationale for the design of different classes of multivalency anti-HIV agents and also discussed the advantages over their monomeric counterparts, providing a novel paradigm to facilitate the development of anti-HIV/AIDS therapeutic agents in treatment of HIV infected community.

Urinary bladder cancer is a common malignancy in industrialized countries. More than 90% of bladder cancer originates in the transitional cells. Bladder transitional cancer prognosis is, according to the most recent definition related to the level of tumor infiltration, characterized by two main phenotypes, Non Muscle Invasive Bladder Transitional Cancer (NMIBC) and Muscle Invasive Bladder Transitional Cancer (MIBC). The genetic profile and the clinical course of the two subtypes are completely different, however among NMIBC the prognosis is not completely predictable, since 20% of the cases experience a relapse, even in the form of MIBC. It has recently been reported that the chromosomal region 12q13-15, containing crucial cancer genes such as MDM2, CDK4, GLI and an entire cluster of HOX genes, is amplified in bladder cancer. HOX genes codify for transcriptionl factor, involved in embryonal development and cancer progression, with main nuclear expression. Particularly it was also described the strong involvement of HOX B13 in several tumors of urogenital system. In this study we have been investigated, by immunohistochemisty and quantitative Real Time PCR, the HOX B13 expression in bladder cancer evolution and progression, evaluating its ability to discriminate between NMIBC and MBCI phenotypes. Cytoplasmic HOX B13 delocalization significantly relates with muscle invasion (p 0.004). In addition in the series of NMIBC nuclear HOX B13 expression loss is significantly associated to shorter disease free survival (p-value=0.038) defining a potential prognostic role. Overexpression of HOX B13 in more aggressive phenotype is also demonstrate at gene level by quantitative RT-PCR. The de-regulation and delocalization of HOX B13 in urinary bladder cancer supports again the important role of HOX genes in tumor evolution and represents a starting point to establish an integrated analysis, in which HOX genes represent important prognostic and predictive markers for bladder cancer.

Methods using fluorogenic peptide substrates have been proposed for screening of proprotein convertase (PC) inhibitors and they are attractive since they offer the advantage of being sensitive, cost-effective and susceptible to miniaturization. Several polyphenols, including epigallocatechin gallate ((-)EGCG), the main component of green tea, and quercetin, widely distributed in fruit and vegetables, however, led to false positive results when fluorogenic peptide substrates were used. Processing of genuine furin substrates was not inhibited by these polyphenols. In the present study, these discordant effects of (-)EGCG on the PC furin were studied. While quercetin can form aggregates in solution, aggregate-based promiscuous inhibition could be ruled out as underlying mechanism for (-)EGCG. Hydrogen peroxide production, from auto-oxidation, was too low to be a major factor but appeared associated to furin inhibition, suggesting a role for other auto-oxidation products. Since the instability of catechins is related to their electrophilic character, we tested the nucleophilic substance glutathione for stabilization. Indeed glutathione reduced furin inhibition and (-)EGCG binding to furin and serum albumin as shown by redox-cycling staining. Catechins, therefore, seem to form reactive compounds and this should be taken into account in screening assays. Adding glutathione to the detergent-based assay, as used in these studies to measure furin processing activity, strongly reduced inhibition by a number of polyphenols (catechins, gallic acid and quercetin), while the effect on the genuine inhibitor nona-D-arginine remained unchanged. In conclusion: the combined use of detergent and glutathione in the screening assay for furin inhibitors improves the predictive value.