Current Medicinal Chemistry - Volume 16, Issue 28, 2009

It has traditionally been accepted that, in the process of cellular differentiation, developmental options are progressively restricted until commitment to a specific fate is established and then only terminal differentiation along this lineage is possible. Although this is usually the case in normal physiological development, the latest experimental evidences indicate that the differentiated state of mature cells is not always as stable and durable as it was thought to be. In fact, recently, a hidden plasticity has been revealed in differentiated cells which allows them to deviate to other cell types that might be, functionally, very far away in other developmental pathways. This plasticity has biological significance since it is necessary for normal development to occur, but it also makes possible the emergence of aberrant lineages when interferences with the normal transcriptional and epigenetic mechanisms in charge of maintaining cellular identity do appear. Cancer is one of the possible outcomes of this aberrant reprogramming. The plasticity of the initial cell suffering the first oncogenic alteration plays an essential role in cancer development, since only if this cell possesses enough plasticity a tumoral reprogramming will be possible and a full-blown tumor will develop. Also, plasticity makes it possible for differentiated cells to acquire cancer stem cell properties in the presence of the appropriate oncogenic insults. In this review we discuss the role of cellular plasticity in the normal development of adult tissues and how cellular susceptibility to reprogramming plays an essential part in cancer development.

Methionine, in addition to its role in protein synthesis, participates in 3 important cellular functions: as AdoMet in transmethylation; as decarboxylated-AdoMet in aminopropylation; as homocysteine its demethylated form, in transsulphuration. Here we provide evidence from the literature and from our own work for a fourth role for its oxoacid: 4- methylthio-2-oxo-butanoate (MTOB) in apoptosis [28,29]. MTOB enters 2 pathways: (a) transamination by glutaminetransaminase K to methionine[13,14].(b)oxidative decarboxylation by the mitochondrial Branched-Chain-Oxo-Acid- Dehydrogenase-Complex to methional and finally to methylthiopropanoyl CoA (MTPCoA) [26,27]. Some of the methional formed after MTOB decarboxylation leaks into the cytoplasm as free methional [29]. Exogenous methional induces apoptosis in normal and cancer cells in culture [28, 29] but not in those overexpressing the antiapoptotic gene bcl2 [30]. In physiologically-induced apoptosis e.g. trophic factor (IL3) withdrawal, methional leakage is decreased [29] suggesting that MTPCoA is also involved in apoptosis. Both methional and MTPCoA give rise to metabolites that may act as cross-linking agents. In the case of methional, the CH3-S moiety is lost and malondialdehyde (MDA) is formed when methional is subjected to •OH attack [29]. MDA generated in situ from 1,3-propanediol, induces DNA-protein cross-linking [41].With regard to MTPCoA, it is metabolized to malonic semialdehyde CoA (MASACoA) with loss of the CH3-S moiety [48,49 ]. The capacity of MASACoA to form cross-links has not yet been established experimentally, but it could be a substrate for one of the histone acyl transferases [50, 51] and so form amides via the CoA at one end and imines by its CHO group at the other, with amino groups on proteins. Chromatin cross-linking/condensation is one of the hall-marks of apoptosis [40]. Methional, MDA and other apoptogenic aldehydes like 4-hydroxy-2-nonenal are oxidized by ALDHs to non-apoptogenic carboxylic acids [29, 44, 45, 68] but retain their apoptotic activity when the ALDHs are inhibited [98, 110]. MASACoA would also lose its cross-linking capacity if its CoA moiety were putatively hydrolysed by ALDHs and/or acylCoA thioesterases [56, 58, 88, 89]. ALDH inhibitors that control cellular MDA and possibly MASACoA homeostasis are cited as examples of targeted therapeutic approaches in chemoresistant cancers [62, 84, 97, 98, 110].

Besides the importance of the renin-angiotensin system (RAS) in the circulation and other organs, the local RAS in the kidney has attracted a great attention in research in last decades. The renal RAS plays an important role in the body fluid homeostasis and long-term cardiovascular regulation. All major components and key enzymes for the establishment of a local RAS as well as two important angiotensin II (Ang II) receptor subtypes, AT1 and AT2 receptors, have been confirmed in the kidney. In addition to renal contribution to the systemic RAS, the intrarenal RAS plays a critical role in the regulation of renal function as well as in the development of kidney disease. Notably, kidney AT1 receptors located at different cells and compartments inside the kidney are important for normal renal physiological functions and abnormal pathophysiological processes. This mini-review focuses on: 1) the local renal RAS and its receptors, particularly the AT1 receptor and its mechanisms in physiological and pathophysiological processes, and 2) the chemistry of the selective AT1 receptor blocker, losartan, and the potential mechanisms for its actions in the renal RAS-mediated disease.

Influenza is a disease for deeply affecting millions of people every year. Recently, there has been considerable concern regarding the highly pathogenic H5N1 avian influenza virus, and its human pandemic potential. With developments in viral biology, there are more novel antiviral strategies targeting these viruses. In this review, we will discuss several proven and potential anti-influenza targets, including viral factors (such as hemagglutinin (HA), M2 ion channel protein, RNA-dependent RNA polymerase (RdRp), nucleoprotein (NP), non-structural protein (NS) and neuraminidase (NA)) and host factors (such as v-ATPase, protease, inosine monophosphate dehydrogenase (IMPDH) and intracellular signalling cascades), and their relevant inhibitors.

Antimicrobial resistance constitutes one of the major threats regarding pathogenic microorganisms. Gramnegative pathogens, such as Enterobacteriaceae (specially those producing extended-spectrum β-lactamases), Pseudomonas aeruginosa, and Acinetobacter baumannii, have acquired an important role in hospital infections, which is of particular concern because of the associated broad spectrum of antibiotic resistance. β-Lactam antibiotics are considered the most successful antimicrobial agents since the beginning of the antibiotic era. Soon after the introduction of penicillin, microorganisms able to destroy this β-lactam antibiotic were reported, thus, emphasizing the facility of pathogenic microorganisms to develop β-lactam resistance. In Gram-negative pathogens, β- lactamase production is the main mechanism involved in acquired β-lactam resistance. Four classes of β-lactamases have been described: A, B, C, and D. Classes A, C, and D are enzymes with a serine moiety in the active centre that catalyzes hydrolysis of the β -lactam ring through an acyl-intermediate of serine, whereas the class B enzymes require a metal cofactor (e.g. zinc in the natural form) to function, and for this reason, they are also referred to as metallo- β-lactamases (MBLs). To overcome β-lactamase-mediated resistance, a combination of β-lactam and a β-lactamase inhibitor, which protects the β-lactam antibiotic from the activity of the β-lactamase, has been widely used in the treatment of human infections. Although there are some very successful combinations of β-lactams and ??-lactamase inhibitors, most of the inhibitors act against class A β-lactamases and remain ineffective against class B, C, and D β-lactamases. This review constitutes an update of the current status and knowledge regarding class A to D β-lactamase inhibitors, as well as a summary of the drug discovery strategy currently used to identify new ??-lactamase inhibitors, mainly based on the knowledge of crystal structure of β-lactamase enzymes.

Variants of the gene of the interleukin-23 receptor (IL23R) were first identified as susceptibility factors in association with inflammatory bowel diseases. Since then it became clear that different variants of the gene play role also in a number of other autoimmune diseases like psoriasis, rheumatoid arthritis, ankylosing spondylitis and multiple sclerosis while in others, like systemic sclerosis, systemic lupus erythematosus or Sjogren syndrome the same effect could not be seen. However, the results are very controversial both in terms of the various polymorphisms and also in population specificity. The aim of the current paper is to overview all available reports on IL23R gene polymorphisms in various autoimmune and inflammatory diseases and to try to give an explanation on the possible effect of the examined variants.

Covering: 1937 to Mar 2008. Caged xanthones, characterized by a unique 4-oxa-tricyclo[4.3.1.03,7]dec-2-one scaffold, are a special class of bioactive components mainly derived from the Garcinia genus (Guttiferae family). Around 100 compounds from this family have been reported to date and most of them have potent antitumor activity, with gambogic acid being the best representative. During the past decades, inspired by the unusual caged skeleton and remarkable bioactivity, scientists from various fields have shown increasing interest on these promising natural products. In this review, the plant resources, structural characteristics, total synthesis, biological activity and mechanisms of action, structure activity relationship, and anticancer drug development of these caged xanthones are described.