Current Molecular Medicine - Volume 10, Issue 1, 2010

Cardiovascular disease is the leading cause of death in the western world. The major contributor of all cardiovascular deaths is myocardial infarction, which often progresses into end-stage heart failure. The loss of cardiomyocytes is a key problem in the development of cardiovascular disease. Two main processes mediate cardiomyocyte loss: necrosis and apoptosis. In contrast to necrosis, apoptosis is a well regulated process essential in normal development and tissue homeostasis. Tight regulation of this process is crucial, especially in post mitotic cells lacking regenerative capacity, like cardiomyocytes. The ubiquitin-proteasome system, accounting for 80 to 90% of intracellular protein degradation, appears to be involved in the regulation of apoptosis. In this process, regulation is performed through the degradation of pro- and anti-apoptotic proteins involved in cell cycle control and specific apoptotic pathways. On the one hand, disturbances in this normally well regulated process are associated with a number of cardiovascular diseases. On the other hand, proteasomal dysfunction may result from ischemia, hypertrophy and heart failure, and a number of cardiomyopathies. This paper reviews the current knowledge on the role of the ubiquitin-proteasome systemmediated regulation of cardiomyocyte apoptosis in cardiovascular disease. Finally, within the ubiquitinproteasome system new molecular targets for treatment of cardiovascular disease are suggested.

Anabolic therapy for osteoporosis has become the most desirable therapeutic option for menopausal osteoporosis. The anabolic agents currently in clinical use are reviewed. Teriparatide (recombinant human 1- 34 parathyroid hormone) is used to treat women with menopausal osteoporosis and men at high risk for fractures. Despite PTH's clinical use, the mechanism underlying its anabolic action requires greater elucidation. Proteol (strontium ranelate) acts by inhibiting bone resorption and presumably promoting bone formation. Though clinical trials have shown that strontium ranelate reduces the frequency of both vertebral and non-vertebral fractures, its molecular target remains controversial. Lately, with the discontinuation of estrogen replacement therapy, phytoestrogens are gaining much attention, chiefly as prophylactic agents. Though ipriflavone stimulates osteoblast function in vitro and favorably influences bone turnover and spinal bone mineral density in peri- and postmenopausal women, its clinical use is currently rather limited. As with PTH and strontium ranelate, the mode of action of ipriflavone requires much greater elucidation. Since osteoporosis therapies are long-term, safety is a major consideration. PTH has been reported to be associated with incidence of osteosarcoma and strontium ranelate with DRESS syndrome. Therefore, target-based (and osteoblast-specific) development of molecules is expected to improve the safety profile of anabolics. Calciumsensing receptor, insulin-like growth factor-1, members of wingless tail signaling family, and sclerostin are emerging concepts in bone anabolic therapy. We will cover the preclinical development of some bone anabolic agents under active investigation.

The Plasmodium falciparum mitochondrion is an organelle that presents structural and physiological characteristics different from mitochondria in other eukaryotes. Moreover, there are substantial differences in the properties of asexual and sexual mitochondria. One of the reasons is the adaptation of the parasite to different environments, in particular the great differences in oxygen tension between the host and the mosquito. In this review, we present a synthesis of the recent data on the ultrastructure, the genome and the physiology of the mitochondrion. We try to clarify the mitochondrial role in the intraerythrocytic environment and particularly focus on mitochondrial metabolic pathways that relate to oxidative phosphorylation, including the tricarboxylic acid cycle, de novo pyrimidine biosynthesis via dihydroorotate dehydrogenase and the particularities of the electron transport chain. In addition, we provide details on certain characteristics like the lack of pyruvate dehydrogenase, the existence of a rotenone-insensitive NADH-dehydrogenase, the possible existence of an alternative oxidase, and uncoupled proteins. Such unique particularities of parasite mitochondria could be promising targets for development of a new therapy. The elucidation of the role of this organelle in microaerophilic respiratory metabolism and the association of antimalarial drugs with hyperbaric oxygen therapy might provide new treatments for infection by P. falciparum.

In developing countries, oral immunization is more readily accepted than parenteral, as it accompanies the ease and safety of administration and induces the desired mucosal immune response against highly infectious pathogen transmitted through mucosal routes. Despite the obvious need and apparent merits, the success in the field of oral vaccination is limited due to factors including harsh gastric environment, enzymatic barrier, intestinal epithelium barrier and the fear of oral tolerance reported in case of mucosal vaccination. The number of strategies has been focused at conquering the mucosal barrier for maximization of the intestinal uptake and stabilization of the biological at all stages before they reach their target. Although, considerable success has been attained using these strategies but none of these have achieved commercial status. Therefore a rationally designed oral vaccine should be successfully delivered to the intestinal mucosal immune cells, and induce both humoral and cellular counterparts of immunity along with the mucosal immune response. The aim of this review article is to describe the recent development in the understanding of the molecular mechanism and implication of gastrointestinal epithelium and cytokines interplay in the induction of immunity and tolerance. The review has been elaborated to discuss the rationale of design of suitable carrier in conjunction with the peculiar necessities of gastrointestinal tract for induction of well balanced immune response.

Osteopontin (OPN) is a matricellular protein that is produced by multiple tissues in our body and is most abundant in bone. It is also produced by cancer cells and plays a determinative role in the growth, progression and metastasis of cancer. Clinically, OPN has been reported to be upregulated in tumor cells per se; this is also reflected by increased levels of OPN in the circulation. Thus, increased OPN levels in the plasma are an effect of tumor growth and progression. Functionally, high OPN levels are determinative of higher incidence of bone metastases in mouse models and are clinically correlated with metastatic bone disease and bone resorption in advanced breast cancer patients. Several research efforts have been made to therapeutically target and inhibit the activities of OPN. In this article we have reviewed OPN in its role as an effector of critical steps in tumor progression and metastasis, with a particular emphasis on its role in facilitating bone metastasis of breast cancer. We have also addressed the role of the host-derived OPN in influencing the malignant behavior of the tumor cells.

Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) that regulates epithelial surface fluid secretion in respiratory and gastrointestinal tracts. The deletion of phenylalanine at position 508 (ΔF508) in CFTR is the most common mutation that results in a temperature sensitive folding defect, retention of the protein in the endoplasmic reticulum (ER), and subsequent degradation by the proteasome. ER associated degradation (ERAD) is a major quality control pathway of the cell. The majority (99%) of the protein folding, ΔF508-, mutant of CFTR is known to be degraded by this pathway to cause CF. Recent studies have revealed that inhibition of ΔF508-CFTR ubiquitination and proteasomal degradation can increase its cell surface expression and may provide an approach to treat CF. The finely tuned balance of ER membrane interactions determine the cytosolic fate of newly synthesized CFTR. These ER membrane interactions induce ubiquitination and proteasomal targeting of ΔF508- over wild type- CFTR. We discuss here challenges and therapeutic strategies targeting protein processing of ΔF508-CFTR with the goal of rescuing functional ΔF508-CFTR to the cell surface. It is evident from recent studies that CFTR plays a critical role in inflammatory response in addition to its well-described ion transport function. Previous studies in CF have focused only on improving chloride efflux as a marker for promising treatment. We propose that methods quantifying the therapeutic efficacy and recovery from CF should not include only changes in chloride efflux, but also recovery of the chronic inflammatory signaling, as evidenced by positive changes in inflammatory markers (in vitro and ex vivo), lung function (pulmonary function tests, PFT), and chronic lung disease (state of the art molecular imaging, in vivo). This will provide novel therapeutics with greater opportunities of potentially attenuating the progression of the chronic CF lung disease.

From the morphogenetic movements of the three germ layers during development to the reactive stromal microenvironment in cancer, tissue interactions are vital to maintaining healthy organ morphologic architecture and function. The stromal compartment is thought to be complicit in tumor progression and, as such, represents an opportune target for disease therapies. However, recent developments in our understanding of the diversity of the stromal compartment and the lack of appropriate models to study its relevance in human disease have limited our further understanding of the role of tissue interactions in tumor progression. The failure of any model to fully recapitulate the complexities of systemic biology continues to create a higher imperative for incorporating various perspectives into a broader understanding for the ultimate goal of designing interventional therapies. Understanding this potential, this review examines the biological models used to study stromal-epithelial interactions and includes an attempt to incorporate behavioral terminology to define and mathematically model ecological relationships in stromal-epithelial interactions. In addition, the current attempt to incorporate these diverse ecological perspectives into in silico mathematical models through cross-disciplinary coordination is reviewed, which will provide a fresh perspective on defining cell group behavior and tissue ecology in disease and hopefully lead to the generation of new hypotheses to be empirically validated.