Current Drug Targets - Volume 15, Issue 4, 2014

Small non-coding microRNAs (miRNAs) regulate gene expression at the post-transcriptional and translational levels. The dysregulated miRNAs are involved in a large variety of diseases including cancer and cardiovascular diseases. MiR-34a is one of the most anti-oncomiRs that is down-regulated in multiple types of cancer. It regulates a wide range of genes and pathways involved in cancer initiation, progression and metastasis. Next to cancer, miR-34a is recently found to be implicated in cardiovascular disease as one damager factor. In this review, we highlight the complex roles of miR-34a in cancer and cardiovascular disease, as well as the therapeutic potentials.

Because of mutation and natural selection, development of drug resistance to the existing antimalarial is the major problem in malaria treatment. This problem has created an urgent need of novel antimalarial drug targets as well as lead compounds. The important characteristic of malaria is that it shows the phenomenon of balanced polymorphisms. Several traits have been selected in response to disease pressure. Therefore such factors must be explored to understand the pathogenesis of malaria infection in human host. Apicoplast, hub of metabolism is present in Plasmodium falciparum (causative agent of falciparum malaria) having similarities with plant plastid. Among several pathways in apicoplast, Dolichol metabolic pathway is one of the most important pathway and has been known to play role in parasite survival in the human host. In P.falciparum, a phosphorylated derivative of Dolichol participates in biosynthesis of glycoproteins. Several proteins of this pathway play role in post translational modifications of proteins involved in the signal transduction pathways, regulation of DNA replication and cell cycle. This pathway can be used as antimalarial drug target. This report has explored progress towards the study of proteins and inhibitors of Dolichol metabolic pathway. For more comprehensive analysis, the host genetic factors and drug-protein interaction have been covered.

5-Lipoxygenase (5-LO) is the key enzyme involved in the synthesis of pro-inflammatory leukotrienes (LTs) and has become a prime target for new drug discovery research and development efforts by the pharmaceutical and biotech industry. The pathophysiological effects of LTs can be modulated by the selective inhibition of 5-LO. In this review, we summarize the established dogma and recent progress on the biochemical and pharmacological regulation of 5-LO and its diverse cellular partners. In the last decade, significant research efforts have led to the exploitation of 5-LO pathway for developing new drugs against inflammatory diseases. Despite few setbacks, a number of promising molecules have moved into clinical development. These fundamental discoveries and proof-of-concept studies will ultimately be helpful in delineating how 5-LO pathway participates in the development of disease phenotype and what are possible key biomarkers of disease progression and regression. Elucidation of molecular mechanism-of-action of 5-LO in individual cell types will pave the way for improving efficacy parameters. Taken together, this combined knowledge about the 5-LO pathway would be helpful in planning collaborative and targeted R&D efforts, by the academic laboratories and pharmaceutical/ biotech industry, for the discovery and development of novel, efficacious and safer drugs against multiple diseases.

Heat shock protein 27 (Hsp27), induced by heat shock, environmental and pathophysiological stressors, is a multidimensional protein that acts as a protein chaperone and an antioxidant. This protein plays a major role in the inhibition of apoptosis and actin cytoskeletal remodeling. This stress-activated protein is up-regulated in many cancers and is associated with poor prognosis as well as treatment resistance by protecting cells from therapeutic agent that normally induces apoptosis. This review highlights the most recent findings and role of Hsp27 in cancer and the different strategies to target and inhibit Hsp27 for clinical purposes.

Differentiated embryo-chondrocyte expressed gene 1 (DEC1) is associated with chondrogenesis, neurogenesis, immune response, biological rhythm, lipogenesis, cell differentiation and carcinogenesis. However, there is little information about its contribution to osteoblast osteogenesis. In the present study, we report that DEC1 expression increases along with the degree of mineralization, which parallells with the increase of osteogenesis induction time in SaoS-2 cells. Dexamethasone (DEX) decreases the osteogenesis capacity such as alkaline phosphatase (ALP) activity and mineralization along with decreasing the DEC1 expression. On the contrary, 17β-estradiol (E2) increases the osteogenesis along with increasing the DEC1 expression. Moreover, the overexpression of DEC1 alone increases the ALP activity and mineralization synchronously, and it not only partially reverses the decrease of ALP activity induced by DEX, but almost abolishes the decrease of mineralized nodules induced by DEX. On the other hand, the DEC1 expression decreases in tibia bone marrow side of ovariectomy mice compared with that in sham-operated mice, and E2 treatment ameliorates the decrease of DEC1 expression induced by bilateral ovariectomy and prevents osteoporosis in ovariectomized mice . Taken together, downregulation of DEC1 expression is related to the decrease of osteogenic capacity. The findings provide a novel target for the therapy of osteoporosis.

Atherosclerosis is now widely recognized as a chronic inflammatory disease that involves innate and adaptive immune responses. Both cellular and humoral components of the immune system have been implicated in atherogenesis. Growing evidence suggests that immune cells play crucial roles in atherogenic plaque formation. Vulnerability of the plaque probably plays an important role in rupture. Most ruptures occur at the periphery of the fibrous cap that covers the lipid-rich core-points where the cap is usually thinnest and most heavily infiltrated by macrophage foam cells. Sudden rupture of a plaque triggers unstable angina, acute myocardial infarction, and sudden cardiac death. Initiation of collagen breakdown in plaques requires matrix metalloproteinase (MMP) family members including MMP-1, MMP-8, and MMP- 13. In addition, other MMPs such as MMP-2, -3, -9, -10 and -12 have also been reported to play roles in atherosclerosis. This review aims to focus on description of general structural features of MMPs and their roles in atherosclerosis.

Huntington’s disease (HD) is the most common polyglutamine neurodegenerative disorder in humans, and is caused by a mutation of an unstable expansion of CAG repeats within the coding region of the HD gene, which expresses the protein huntingtin. Although abnormal protein is ubiquitously expressed throughout the organism, cell degeneration occurs mainly in the brain, and there, predominantly in the striatum and cortex. The mechanisms that account for this selective neuronal death are multifaceted in nature and several lines of evidence suggest that mitochondrial dysfunction, overproduction of reactive oxygen species (ROS) and oxidative stress (an imbalance between pro-oxidant and antioxidant systems resulting in oxidative damage to proteins, lipids and DNA) might play important roles. Over time, this can result in the death of the affected neuronal populations. In this review article we present an overview of the preclinical and clinical studies that have indicated a link between oxidative stress, neurodegeneration, and cell death in HD. We also discuss how changes in ROS production affect neuronal survival, highlighting the evidence for the use of antioxidants including essential fatty acids, coenzyme Q10, and creatine, as potential therapeutic strategies for the treatment of this devastating neurodegenerative disorder.

Monoclonal antibody-based treatments of cancer which serve as magic ‘bullets’ have been established as one of the most successful therapeutic strategies. A variety of antigens has been investigated as targets for the mAb therapy of gastric cancer, including the carbohydrate type 2 blood group antigen. Lewis Y (LeY) is overexpressed on tumor cells surface either as glycoproteins or glycolipids. LeY is difucosylated oligosaccharide with the chemical structure [Fucα1,2Galβ1→4(Fucα1,3)GlcNAcβ1→R], which is catalyzed by fucosyltransferases, such as FUT1 (α1,2) and FUT4 (α1,3). The role of LeY antigen in cancer treatment and prevention has been extensively studied. Moreover, the cyclooxygenase- 2 (COX-2) is an early event protein, highly expressed in H. pylori-related gastric cancer. COX-2 may play a pivotal part in the maintenance of tumor viability, growth, and metastasis. The COX-2 is upregulated in a variety of cancers, including gastric cancer. However, its inhibition may prevent or reverse gastric carcinogenesis. H. pylori mediated alteration of COX-2 through MAPKs pathway is one of the mechanisms that is implicated in gastric cancer. We have found COX-2 and LeY to be correlative sources of specific gastric biomarkers in gastric cancer, which is upregulated in the gastric cancer through MAPKs pathway. In addition, the anti-LeY antibody significantly downregulated the COX-2 expression through MAPKs pathway, helpful to the treatment of gastric cancer. In this review, we summarize the therapeutic effect of anti-LeY antibody, including the crucial role of COX-2 and LeY antigen in gastric cancer and discuss the COX-2 inhibition by anti-LeY antibody through MAPKs pathway.