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Current Drug Therapy (v.3, #3)

Current Advances in the Development of Anticancer Drugs Targeting Tyrosine Kinases of the Src Family by Silvia Schenone, Samantha Zanoli, Chiara Brullo, Emmanuele Crespan, Giovanni Maga (pp. 158-176).
Protein kinases, either membrane-embedded receptorial or cytosolic non-receptorial ones, are important transducers of cell proliferation signals. In almost all tumor cells, the activity of some kinases is deregulated, either because of the presence of cancer-specific aberrant forms, or as a consequence of alterations in regulatory pathways, at the transcriptional or post-transcriptional level, which increase the activity of protein kinases with respect to normal cells. The study of the non-receptor tyrosine kinase Src plays a pivotal role in the field of the molecular genetics of cancer. The Src family of kinases (SFKs) comprises nine members, Src, Fyn, Yes, which are expressed in most tissues, and Blk,Yrk, Fgr, Hck, Lck and Lyn, which are more selectively expressed in particular tissues. To date, cellular (c-) Src has been implicated in the development of human cancer. Like oncogenic v-Src, activated mutants of c-Src can transform cells in culture and induce tumours in chickens. In addition, Src protein expression and/or activity is elevated in epithelial cancers, or cell lines derived from these, and there is often an association with advancement of disease or with malignancy. During the past decade, examples of tyrosine kinases inhibitors have been reported. Many of these compounds were highly active in vitro, but only a few demonstrated in vivo activity. These approaches led to the characterization of the PP1/PP2 derivatives as very strong and selective inhibitors of the c-Src family of kinases. Unfortunately, attempts to improve the biological profile of the latter compounds have so far met little success. Following these studies, some other inhibitors, possessing different chemical structures and interesting c-Src inhibitory activity, have been recently reported. Some of these molecules showed potent inhibition of tumor cell proliferation, which was due to the interference with the signalling pathway at the level of Src tyrosine kinase, providing proof-of-principle for the targeting of Src in anticancer chemotherapy.

New Targets for Therapy in Polyglutamine (polyQ) Expansion Diseases by Lorena Perrone, Mariarosa Melone (pp. 177-189).
The polyglutamine (polyQ) repeat disorders are a family of inherited disorders characterized by progressive neurodegeneration, as well as the formation of intracellular protein aggregates. Huntington's disease (HD) is the most prevalent disorder in the family of polyQ diseases. This family includes nine other neurodegenerative disorders: Dentatorubral- pallidoluysian atrophy (DRPLA), Bulbo-Spinal Muscular Atrophy (BSMA) and Spinocerebellar ataxia (SCA) types 1-3, 6, 7, 12 and 17. Each disease is caused by the expansion of a tract of repeated CAG triplet in a distinct gene, causing transcription of proteins with lengthened polyQ repeats. Although mutations occur frequently in a ubiquitously expressed gene, neurodegeneration occurs in a specific cell type. The mutant proteins involved in polyQ disease are unrelated and they share only the glutamine extension. As for the pathogenic mechanism by wich the repeat expansion leads to the disease, major models include a loss of function of the gene and a gain of function by the mutant RNA transcript or protein product. Indeed, altered function in the ubiquitin-proteasome system (UPS), endoplasmic reticulum (ER) and mitochondria function, as well as a primary failure in autophagy has been demonstrated. However, the pathogenic mechanism varies from one disease to another, depending on the motif, length, and intragenic location of the repeat. Understanding the molecular mechanisms of repeat instability and pathogenic process is not only of scientific interest but also essential for the development of rational treatment of these diseases.

Who's Winning the War? Molecular Mechanisms of Antibiotic Resistance in Helicobacter pylori by Kathleen Jones, Jeong-Heon Cha, D. Merrell (pp. 190-203).
The ability of clinicians to wage an effective war against many bacterial infections is increasingly being hampered by skyrocketing rates of antibiotic resistance. Indeed, antibiotic resistance is a significant problem for treatment of diseases caused by virtually all known infectious bacteria. The gastric pathogen Helicobacter pylori is no exception to this rule. With more than 50and#x25; of the world's population infected, H. pylori exacts a tremendous medical burden and represents an interesting paradigm for cancer development; it is the only bacterium that is currently recognized as a carcinogen. It is now firmly established that H. pylori infection is associated with diseases such as gastritis, peptic and duodenal ulceration and two forms of gastric cancer, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. With such a large percentage of the population infected, increasing rates of antibiotic resistance are particularly vexing for a treatment regime that is already fairly complicated; treatment consists of two antibiotics and a proton pump inhibitor. To date, resistance has been found to all primary and secondary lines of antibiotic treatment as well as to drugs used for rescue therapy.

Therapy and Further Development of Anti-Leishmanial Drugs by Joana Pinto da Costa Tavares, Ali Ouaissi, Anabela Cordeiro-da-Silva (pp. 204-208).
Leishmaniasis is a parasitic infection that affects millions of people worldwide, especially in tropical and subtropical areas, and is responsible for high mortality and morbidity. The therapies available up to the present are far from satisfactory and, since leishmaniasis affects poor people in poor regions, the development of new drugs has been neglected due to the lack of commercial motivation. Safe and orally available drugs, especially against the visceral form of the disease, are needed. An overview of the main strategies for antileishmanial drug development, mainly focused on the target-based drug development approach, is given.

Nanogel Engineered Polymeric Micelles for Drug Delivery by Supriya Shidhaye, Vishwanath Lotlikar, Sheetal Malke, Vilasrao Kadam (pp. 209-217).
In the past few decades nanotechnology for drug delivery has attracted a great deal of attention. Nanogels under this category are sub-micron sized water swellable crosslinked structures of biocompatible hydrophillic polymers which have wide array of applications in drug delivery, biotechnology and biomedical field due to their nanosized structure with characteristics of nanoparticles and hydrogels. Nanogels are synthesized by emulsion polymerization, photopolymerization, pulse radiolysis, photo-Fenton reaction and physical self-assembly techniques. Nanogels are characterized by various microscopic techniques like scanning electron microscopy, atomic force microscopy and analytical techniques such as dynamic light scattering, zeta potential, fluorescence, nuclear magnetic resonance, size exclusion chromatography. Nanogels can trap novel nanobiomaterials and find application in delivery of proteins, peptides, gene delivery, insulin delivery, and as toxic scavengers. Thus nanogels can act as a carrier as well as sustained release can be achieved by designing responsive nanogels such as pH, thermo, photo or magneto-responsive nanogels. Thus the article focuses on the synthesis, characterization and applications of nanogels.

Sphingomyelinase Inhibition Suggests a Possible New Strategy for the Treatment of Inflammatory Bowel Disease by Shinji Soeda, Akira Sakata, Takashi Ochiai, Kazuya Yasuda, Yukako Kuramoto, Hiroshi Shimeno, Akihisa Toda, Reiko Eyanagi, Sadao Hikishima, Tsutomu Yokomastu, Shirashi Shibuya (pp. 218-225).
Multiple lines of evidence suggest that macrophages have a critical role in the disease pathology of inflammatory bowel disease (IBD) by secreting inflammatory cytokines, such as tumor necrosis factor (TNF)-and#945;, interleukin (IL)- 1and#946;, IL-6 and IL-8. Therapies for IBD target one or more of these inflammatory mediators. Recent advances in drug development for IBD have involved the use of monoclonal antibodies to inhibit specific inflammatory cytokines. In particular, the anti-TNF-and#945; antibodies, CDP571 and Infliximab have been used clinically to treat Crohn's disease with some success. The inflammatory cytokines and lipopolysaccharide (LPS) cause activation of sphingomyelinases (SMases) and subsequent hydrolysis of sphingomyelin (SM), to generate a lipid messenger ceramide. The design of SMase inhibitors may offer new therapies for the treatment of LPS- and cytokine-related IBD. We synthesized a series of difluoromethylene analogues of SM (SMAs). This review discusses recent data from our laboratories on the effects of the most potent SMase inhibitor, SMA-7, on the LPS-mediated releases of the cytokines from macrophages and intestinal epithelial cells and the pathology of dextran sulphate sodium (DSS)-induced colitis in mice. Our findings suggest a central role of SMase/ceramide signaling in the pathology of DSS-induced colitis in mice, indicating a possible preventive or therapeutic role for SMase inhibitor in IBD.

Genetically Modified Hepatitis B Surface Antigen: A Powerful Vaccine Technology for the Delivery of Disease-Associated Foreign Antigens by Scott Thomson, Oscar Haigh, Allan Gould, Robert Tindle (pp. 226-234).
The surface antigen of hepatitis B virus (HBsAg) spontaneously aggregates into and#x2018;emptyand#x2019; virus-like particles (VLPs) in the absence of other viral components. The powerful immunogenicity of HBsAg when administered either as VLPs or as naked DNA invites it's exploitation as a vector for the delivery of antigenic determinants from other organisms. Here we discuss ways in which HBsAg may be modified to derive vaccines against disease-related pathogens. We review studies demonstrating the induction of disease-protective antibody and T-cell responses induced by immunization with recombinant HBsAg vaccines, and consider how these vaccines might best be delivered. Unmodified HBsAg VLPs are licensed for use in humans as the pan-global vaccine to prevent hepatitis B virus infection, suggesting that route-tomarket for recombinant HBsAg vaccines might be simplified.
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