Current Drug Targets - Volume 10, Issue 6, 2009

Glycosylation of proteins on asparagine amino acids (N-linked) in proteins of eukaryotic cells is initiated by the biosynthesis of dolichol-pyrophosphate-N-acetylglucosamine from dolichol-phosphate and UDP-N-acetylglucosamine. The enzyme catalyzing this reaction, UDP-GlcNAc:Dolichol Phosphate GlcNAc-1-Phosphate Transferase (DPAGT1), has been further characterized in several cell types with respect to its gene, gene products, membrane topology, functional sites, lipid dependence, and metabolic regulation. This review summarizes these properties as an update from an earlier detailed and critical review by Lehrman (Lehrman, M. A. (1991) Glycobiology, 1, 553-562).

The sialyltransferase family represents a group of enzymes that transfers sialic acid from its common nucleotide sugar donor, CMP-NeuAc, to the terminal carbohydrates group of various glycoproteins and glycolipids. Cloning of these enzymes from mammalian sources indicated these are all type II membrane proteins with topological features common to other glycosyltransferases. To date, 20 cloned enzymes with distinct substrate specificity have been obtained for mammalian sialyltransferases. These account for four subfamilies according to the carbohydrate linkages synthesized, namely, ST3Gal, ST6Gal, ST6GalNAc, and ST8Sia. Comparative peptide sequence analysis of these cloned enzymes showed the presence of four conserve sialylmotifs, namely ‘L’- (for long), ‘S’- (for short), -‘III’ (for being third position in sequence) and ‘-VS’ (for very small), common to all of this protein family. Experiments by site-directed mutagenesis showed evidence that these motifs contribute to the binding of either donor or the acceptor or both. While the Lsialylmotif contributes to the binding of the donor substrate, the motifs -III and -VS contribute to the binding of the acceptor substrate. S-sialymotif, on the other hand, contributes to the binding of both the donor and acceptor substrates. Apparently, a disulfide linkage between the L-sialylmotif and the S-sialylmotif bringing all of these motifs closer together facilitates such interaction with the substrates. In addition, although with no experimental evidence, comparative sequence analysis also suggests a strong correlation of linkage specificity of these enzymes with the peptide sequence closer to these sialylmotifs.

In the current era, more complex cardiac surgical procedures are being performed on elderly patients with variety of co-morbid conditions, which increases the demand to further improve the outcome of cardiac surgery. The role of insulin therapy in improving cardiac surgical outcomes has long been studied. However, the more recent evidence suggests that the entire potential of the insulin therapy has not yet been fully disclosed. The aim of this paper is to review different aspects of insulin therapy including different protocols used, timing of therapy and the objective glycemic target levels with its effect on improving cardiac surgical outcomes.

Purpose of Review: This review summarizes the current state of knowledge on non-alcoholic fatty liver disease (NAFLD) and the hepatitis C virus (HCV)-associated liver fibrosis, and provides insight into the role of dysmetabolism in hepatic fibrogenesis. Clinical relevance of drugs correcting these metabolic disturbances in the reversion of liver fibrosis will also be discussed. Recent Findings: Liver fibrosis affects more than ten millions of people worldwide and may lead to cirrhosis, liver failure, and death. Recent epidemiological data indicate that the incidence of liver fibrosis is expected to triple during the next 10 to 15 years as a result of the HCV infection and NAFLD escalation. In accordance with the modern view of liver fibrogenesis, the pathways involved in the pathogenesis of hepatic fibrosis appear to be broadly similar regardless of the etiology. Summary: Some features of metabolic syndrome, including obesity, insulin resistance, and type 2 diabetes represent a strong risk factor in development and progression of hepatic fibrosis. However, whatever the cause, fibrosis culminates in cirrhosis and results in liver failure, thus, a potent anti-fibrotic therapy is urgently needed to reverse scarring and eliminate progression to cirrhosis.

Myocardial infarction and stroke are exaggerated by rupture of atherosclerotic lesions. Rupture-sensitive plaques have a specific composition which renders them vulnerable, but additional factors (acute infection, higher sympathetic activity, excessive increase of blood pressure or exposure to a variety of drugs) are needed to set off the event. Toll-like receptors are important components of the innate and adaptive immune system and seem to be a potential link between inflammation, infectious disease and atherosclerosis. In addition to classical bacterial and viral antigens, several endogenous ligands (HSP, ox-LDL, apoptotic cells) have also been proposed to react to TLRs. There is accumulating evidence substantiating the contribution of the TLR-signaling pathway not only in the initiation but also in the progression of atherosclerosis. TLRs also play a key role in the development of tissue ischemia. Apoptosis and inflammation comprise two important indicators of plaque instability, and trigger factors augmenting rapidly TLR signaling can lead to aggravation of plaque-rupture. Due to their multiplex involvement in ischemic conditions, Toll-like receptors may be a promising target for therapeutic intervention. In situations such as acute coronary syndrome, in which inhibition of the inflammatory cascade is warranted, the administration of TLR-blocking agents as adjuvant therapy and the clinical usefulness of this association should be considered.

The recently described complication of late and very late stent thrombosis with coronary stents has raised the question of when is it safe to stop antiplatelet therapy in the era of drug eluting stents? With several million patients having already had coronary stents implanted worldwide, the importance of an appreciation of stent thrombosis is not only critical to the cardiologist but also surgeon, physician, dentist and other specialists that perform procedures on patients which require with-holding antiplatelet agents. Currently there is great concern amongst medical professionals on how to manage this group of patients in the absence of clear guidelines. This article reviews the current data on coronary stents, in-stent restenosis and stent thrombosis and role of antiplatelet medication post percutaneous coronary intervention (PCI) to provide a concise and clear algorithm for managing perioperative antiplatelet therapy in patients having undergone recent PCI. The algorithm encourages a multidisciplinary approach and is based on the surgical bleeding risk, operative risk of adverse cardiac events and stent thrombosis risk to guide safe practice. Challenging areas including aspirin and clopidogrel hypersensitivity, clopidogrel resistance and concomitant vitamin K antagonist therapy are also addressed.

Imatinib mesylate is currently the standard therapy for chronic myeloid leukemia (CML) patients. Despite the remarkable results achieved with imatinib, the emergence of resistance to this drug has become a significant problem. Several strategies have been developed to overcome imatinib resistance, including dose escalation of the drug, combination treatments or novel targeted agents. Nilotinib is a second-generation tyrosine kinase inhibitor 30-50 fold more potent than imatinib with high affinity and selectivity on BCR/ABL, active against a wide range of mutant clones, except T315I mutation. Phase II trials of nilotinib showed high activity in imatinib-resistant or intolerant CML patients; front-line treatment of chronic phase Ph+ CML demonstrated rapid and stable cytogenetic responses and increasing molecular responses. We here review the development of nilotinib and the efficacy data in phase II and front-line trials.

HER2 (v-erb-b2 erythroblastic leukemia viral oncogene) is a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. Since the discovery of a role for HER2 and other EGF receptors in the development and progression of cancer, they have become targets for a number of targeted anti-cancer drugs. These drugs have proven to be effective in treating and managing a range of cancers, however, recent observations in the clinic have suggested that their administration causes many toxicities, including gastrointestinal toxicity. Drugs with HER2 inhibitory activity fall into two categories; the monoclonal antibodies and small molecule tyrosine kinase inhibitors. Both of these drug classes have been shown to induce symptoms consistent with mucositis development; including nausea and vomiting, diarrhoea and abdominal pain. However, to date, limited studies have been carried out to justify the source of these toxicities. This review summarizes our current knowledge of the toxicities associated with commonly used HER2 targeted therapy drugs, the role of HER2 in cancer and the healthy gastrointestinal tract and the possible mechanisms by which drugs with HER2 inhibitory activity can induce gastrointestinal damage and possibly mucositis in patients.

Osteoarthritis (OA) is the most common rheumatic pathology. It is related to aging, and is characterized mainly by cartilage degradation. Despite its high prevalence, currently available therapy is limited and focused on treating pain, which is the principal symptom of OA. Therefore, new treatments for OA that slow the progression of the disease are urgently needed. Because the progression of OA involves different tissues and complex biological processes, ongoing research is attempting to increase our knowledge of OA pathogenesis. New approaches for the characterization of molecules that play a role in OA have recently emerged. These include genomic, proteomic and metabolomic technologies. These techniques, coupled with sophisticated statistical methods, permit the simultaneous analysis of multiple targets, and have become very powerful tools in OA research. It is believed that proteomics will soon provide a much-needed novel therapeutic approach to treating OA. At present, many quantitative proteomics studies on the matrix metalloproteinases have led to the characterization of a plethora of new matrix metalloproteinase substrates while pharmaco-proteomics approaches have provided valuable information for target validation. This review will focus on the utility of proteomics for gaining insight into OA pathogenesis, identifying new therapeutic targets, and developing novel treatments.

Calcineurin inhibitors remain the mainstay of immunosuppression in liver transplantation but are associated with important side effects such as diabetes, hypertension and nephrotoxicity which can influence quality of life and survival rates. A variety of non-calcineurin inhibitors have been used in liver transplantation, either during induction immunosuppression in an attempt to delay the introduction of calcineurin inhibitors or during maintenance immunosuppression with reduced dose calcineurin inhibitors to minimize calcineurin inhibitor toxicity while preserving hepatic allograft function. With few exceptions, single agent immunosuppression with non- calcineurin inhibitors has not been universally practiced outside of clinical trials due to unacceptably high rates of hepatic allograft rejection. Although several single center studies have reported encouraging results with these new agents when used with reduced dose calcineurin inhibitors, large, randomized studies are eagerly awaited. Furthermore, as the impact of these newer agents on the recurrence of hepatitis C continues to evolve, clinicians need to be prudent with their use until data from controlled studies is available. This article will review currently used immunosuppressants in liver transplantation, novel therapies in development and the impact of these medications of the recurrence of hepatitis C after liver transplantation.

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Due to an overlook, the sequence of authors name of the manuscript entitled “One century of triglycerides, but there is still lots to learn!” published in the journal Current Drug Targets - Volume 10, Issue 4 (pg. 299-301), 2009 was mistakenly printed as Anagnostopoulou K, Kolovou G, Mikhailidis DP. The correct sequence of authors name is Kolovou G, Anagnostopoulou K, Mikhailidis DP.