Current Medicinal Chemistry - Volume 14, Issue 27, 2007

Stress or heat shock proteins (Hsps) Hsp90, Hsp70 and Hsp27 are chaperones that assist the proteins in their folding, stability, assembly into multi-protein complexes and transport across cellular membranes. The expression of some of them is highly induced in response to a wide variety of physiological and environmental insults. Hsps have a dual function depending on their intracellular or extracellular location. Intracellular Hsps have a protective function. They allow the cells to survive to lethal conditions. The cytoprotective functions of Hsps can largely explain by their anti-apoptotic properties. Hsp90, Hsp70 and Hsp27 can directly interact with different proteins of the tightly regulated programmed cell death machinery and thereby block the apoptotic process at distinct key points. In cancer cells, where the expression of Hsp27, Hsp70 and/or Hsp90 is frequently abnormally high, they participate in oncogenesis and in resistance to chemotherapy. Therefore, the inhibition of Hsps has become an interesting strategy in cancer therapy. In contrast to intracellular Hsps, extracellular located or membrane-bound Hsps mediate immunological functions. They can elicit an immune response modulated either by the adaptive or innate immune system. In cancer, most immunotherapeutical approaches based on extracellular Hsps exploit their carrier function for immunogenic peptides. This review will discuss this different and often paradoxical approaches in cancer therapy based on the dual role of Hsps, protective/tumorigenic versus immunogenic.

Alzheimer's disease (AD) is the most prevalent form of dementia, and its effective disease modifying therapies are desperately needed. Promotion of non-amyloidogenic alpha (α)-secretase cleavage of amyloid precursor protein (APP) to release soluble sAPPα, based on the most widely accepted “amyloid model” as a plausible mechanism for AD treatment, is the focus of this review. Modulation of α-secretase or “a disintegrin and metalloprotease (ADAM)”s activity via protein kinase C (PKC), calcium ion (Ca2+), tyrosine kinase (TK), MAP kinase (MAPK), and hormonal signaling, which regulate catabolic processing of APP, are discussed. The inhibition of amyloidogenic processing of APP by the beta (β)-and gamma (γ)-secretase has been considered till now a promising strategy to treat AD. But β- and γ-secretase inhibitors, along with the available therapeutic tools for AD, have side effects. These challenges can be circumvented to certain extent; but activation of sAPPα release appears to be a potential alternative strategy to reduce cerebral amyloidosis. Drug screens have been performed to identify therapeutics for AD, but an effective screening strategy to isolate activators of α-secretase has been rarely reported. Novel reporter-based screens targeted toward APP mRNA 5' untranslated region (UTR), followed by counterscreens to detect α-secretase stimulators, could be important in detecting compounds to promote sAPPα release and reduce amyloid beta (Aβ) buildup. The primary inflammatory cytokine interleukin-1, which stimulates APP 5'UTR-directed translation of cell-associated APP, enhances processing to sAPPα in astrocytes and co-activates ADAM-10/ADAM-17 through MAPK signaling; thus illustrating a novel pathway that could serve as therapeutic model for AD.

Alzheimer's disease (AD) is the leading cause of dementia. Although the etiology of AD remains controversial, the amyloid hypothesis suggests that β-amyloid (Aβ) peptides may contribute to brain dysfunction, and microglial activation has become increasingly regarded as a potential contributor to disease pathogenesis. Microglial activation is characterized by morphological changes and by production of various effectors, and activated neuroinflammation concurrent with increased oxidative stress may contribute to damage to neurons. However, recently there has been a recognition that microglia may also play a neuroprotective role through their release of neurotrophic factors and through phagocytosis of Aβ. Thus, there is growing consensus that a favorable combination of diminished microglia- mediated neuroinflammation and enhanced Aβ clearance may be critical in AD therapy. In this review, we will discuss the role of microglial activation in AD and how pharmacologic manipulation of microglia might bear upon the treatment of AD.

Neuraminidase is a major glycoprotein of influenza virus which is essential for viral infection and offers a potential target for antiviral drug development. Rational drug design of NA inhibitors is now in the clinic and these molecules are effective and safe for the treatment of influenza. Recently, research of structure-based NA inhibitors is becoming an interesting field, leading to a breakthrough in the control of influenza. Here we review the progress in the rational drug design of NA inhibitors in recent years.

In multicellular organisms, unnecessary or harmful cells, such as those that are cancerous or infected with a virus, are eliminated by apoptosis. After apoptosis, cell corpses are rapidly recognized and phagocytosed by professional phagocytes, such as macrophages and dendritic cells. The rapid removal of cell corpses by phagocytes prevents the release of potentially toxic or immunogenic materials from dying cells. Although a number of molecules on phagocytes have been found to be involved in apoptotic cell clearance in vitro, only a few have been proved to be involved in apoptotic cell clearance in vivo by analyses of knockout animals. These knockout mice commonly suffer from autoimmunity, indicating that the complete removal of apoptotic cells is essential for the maintenance of selftolerance. In this review, we present an overview of the molecular mechanisms of apoptotic cell clearance by phagocytes and the pathological relevance of the failure of apoptotic cell clearance to autoimmune disorder.

Topical immunization (TI) is novel and needle free strategy involving vaccine delivery through topical application of antigen and adjuvant(s) directly or via a suitable carrier system on intact skin. Anatomy and physiology of skin attracts scientists in developing topical carrier system(s) for enhanced delivery of bioactive(s). Numerous techniques i.e. physical, chemical and vesicular carrier systems have been exploited for topical immunization. The present review discuss various vesicular systems i.e. liposomes, niosomes, transfersomes, vesosomes etc. for the efficient topical delivery of various immunogens along with comparative points of their merit(s) in TI. The mechanism of permeation of bioactive(s) through skin route via these carriers to the immune system for development of both cellular and humeral immunity has also been discussed. Moreover, the effect of composition and type of carrier system on type of immunity induced has also been focused to develop new effective carrier system(s) for topical immunization.

The wide biochemical diversity of glycolipids in membranes explains why these molecules are often selected by pathogens (viruses, bacteria, prions) as primary sites of interactions with the cell surface. Moreover, glycolipids concentrate into cholesterol/ glycolipid-rich microdomains where they can reach high local concentrations consistent with the multivalent attachment of pathogens on the cell surface. Finally, recent studies have shown that glycolipids could also modulate protein conformation. This chaperone activity of glycolipids has been associated with various pathogenic processes including HIV infection, prion propagation, and amyloid aggregation in Alzheimer's and Creutzfeldt-Jakob's diseases. Despite the potential interest for drugs mimicking glycolipid structure and function, the physicochemical properties of authentic glycolipids suggested that it might be difficult to obtain synthetic glycolipid analogues able to neutralise those pathogens before they could reach the cell surface. Recent data obtained with mono-, di-, and trihexosylceramide (GalCer, LacCer and Gb3) have proven that this was absolutely not the case and that highly active inhibitors could be designed through slight modifications of glycolipid structure. Biochemical studies of glycolipid-protein interactions have highlighted the importance of CH- π stacking interactions between galactosyl head groups of the glycolipid and aromatic amino acids of the protein. The discovery of this unique mechanism of interaction may allow a rational strategy for the design and synthesis of glycolipid-based molecules as new anti-infectious and/or anti-amyloidogenesis compounds. This strategy, which takes into account the hierarchical organisation of glycolipids into discrete membrane microdomains as well as their association with cholesterol, is discussed in the present review.

Women have a higher percentage of body fat than men, and there is a gender-specific difference in fat distribution: Females tend to accumulate fat around the hips, buttocks, and thighs while men have a larger intra-abdominal (visceral) fat mass. After menopause, there is a redistribution of fat depots, and post-menopausal women develop increased amounts of visceral fat. The risk of developing obesity-related diseases is significantly lower in pre-menopausal women compared to men, a difference that is abolished after menopause, suggesting that the female sex steroid estrogen influences adipogenesis and adipose metabolism. Experimentally, estrogen increases the size and number of subcutaneous adipocytes and attenuates lipolysis. Post-menopausal women also develop a more atherogenic lipid pattern and decreased levels of the prothrombotic protein plasminogen activator inhibitor-1, which attenuates fibrinolysis. Pathologically increased circulating cortisol concentration is associated with dysmetabolic features e.g., central obesity, elevated blood pressure, insulin resistance, and dyslipidemia. In “simple obesity,” glucocorticoid production is elevated. Peak levels of circulating cortisol are however low or normal, possibly because of increased clearance and/or tissue-specific changes in cortisol production. In addition to the adrenal production of cortisol, cortisol is also generated in adipose tissue by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) which converts inactive cortisone to active cortisol. The enzyme activity in subcutaneous fat increases with increasing body weight. Estrogen seems to have a tissue-specific influence on 11βHSD1 enzyme activity, attenuating it in liver, kidney, and testis but upregulating 11βHSD1 mRNA expression in preadipocytes from women. In the present review, we summarize and discuss the interaction between glucocorticoids and sex steroids and their influence on adipocyte metabolism.

The blood protein fibrinogen as a ligand for integrin and non-integrin receptors functions as the molecular nexus of coagulation, inflammation and immunity. Studies in animal models and in human disease have demonstrated that extravascular fibrinogen that is deposited in tissues upon vascular rupture is not merely a marker, but a mediator of diseases with an inflammatory component, such as rheumatoid arthritis, multiple sclerosis, sepsis, myocardial infarction and bacterial infection. The present article focuses on the recent discoveries of specific cellular targets and receptors for fibrinogen within tissues that have extended the role of fibrinogen from a coagulation factor to a regulator of inflammation and immunity. Fibrinogen has the potential for selective drug targeting that would target its proinflammatory properties without affecting its beneficial effects in hemostasis, since it interacts with different receptors to mediate blood coagulation and inflammation. Strategies to target receptors for fibrinogen and fibrin within the tissue microenvironment could reveal selective and disease-specific agents for therapeutic intervention in a variety of human diseases associated with fibrin deposition.

Hearing loss (deafness) affects approximately 250 million people globally. The major cause of deafness is loss of hair cells and spiral ganglion neurons due to aging, antibiotic use, noise exposure, and genetic defects. At the present time, there is no effective method for restoration of hearing biologically. Cochlear stem cells/progenitors (CSCs), quiescent in the organ of Corti, are excellent candidates for restoration of cell types in the organ of Corti biologically. However, little is known about the biology of CSCs and developmental cues for CSCs to differentiate into hair cells and neurons at the present time. In this article, we briefly reviewed the isolation of CSCs from the postnatal organ of Corti in mice and their capability to differentiate into hair cells and neurons in vitro under the guidance of a group of growth factors: sonic hedgehog (SHH), epidermal growth factor (EGF), retinoic acid (RA), and brain-derived neurotrophic factor (BDNF), herein termed SERB. The identification of CSCs and their differentiation signals is potentially of clinical importance.

In our review entitled ‘Myocardial Ischemia-Reperfusion Injury, Antioxidant Enzyme Systems, and Selenium: A Review’ in the Current Medicinal Chemistry, 2007, 14, 1539 -1549. We wish to correct a mistake in the authorship of the manuscript. It should be read as: Myocardial Ischemia-Reperfusion Injury, Antioxidant Enzyme Systems, and Selenium: A Review Kylie M. Venardos1, Anthony Perkins2, John Headrick2, David M. Kaye*,1 1Wynn Department of Metabolic Cardiology, Baker Heart Research Institut