Current Medicinal Chemistry - Volume 19, Issue 35, 2012

Infection with Human Immunodeficiency Virus (HIV) remains a global public health problem. Although the epidemic has not been completely controlled, there was considerable progress in HIV prevention and treatment during the last 30 years. The modern prevention approaches are multi-component including also the administration of combinations of potent antiretroviral agents as a prophylaxis after occupational or non-occupational exposures to HIV. The aim of the current review is to present the chemical and pharmacological characteristics of antiretroviral drugs used in HIV prophylaxis and to describe briefly the medical management of exposures to potentially infectious body fluids.

Reactivation of hepatitis B infection (HBV) is known to occur in liver graft recipients and in chronic carriers of the surface antigen of HBV who receive immunosuppressive therapy. The use of hepatitis B immune globulin alone or in combination with antiviral agents such as lamivudine, adefovir, tenofovir, entecavir, famciclovir, ganciclovir, as prophylaxis in HBV liver transplants, has been well documented. In terms of HBV positive carriers undergoing cytotoxic chemotherapy, the preemptive use of nucleoside or nucleotide analogues seems to be effective. Monotherapy or combination of antiviral drugs, as well as the optimal duration of HBV prophylaxis, is to be determined.

Current data about the role of adamantanes and neuraminidase inhibitors (NIs) in the chemoprophylaxis against influenza viruses were reviewed. We found significant evidence favouring the role of NIs in the chemoprophylaxis of influenza. Awareness and prudent use are necessary, due to recent evidence of gradually increasing resistance of several influenza strains to these agents. On the other hand, the role of adamantanes appears to have decreased over the last decade. Both pre-pandemic and the novel pandemic A/H1N1 2009 strains exhibited either increasing rates of resistance or no susceptibility to adamantanes. Adamantanes currently only have a theoretical role in influenza chemoprophylaxis given the likelihood of the occurrence of an epidemic due to a susceptible strain. In conclusion, changes in antiviral susceptibility will affect future guidance in prophylaxis against influenza. Further investigation of novel medications with new mechanisms of action is important in this regard. Meanwhile, implementing strategies to conserve our current antivirals is necessary.

Human Cytomegalovirus is a commonly identified herpesvirus that establishes a state of latent infection in the majority of the population by adulthood. A coordinated immune response involving both the innate and adaptive immune system prevents active viral replication and disease. Cellular immunity appears particularly important to control of viremia requiring both a CMV-specific CD4+ and CD8+ T cell response. Solid organ transplant recipients are particularly susceptible to CMV related disease due to the immunosuppression necessary to prevent organ rejection, with patients receiving T cell depleting therapies being at highest risk. The deleterious outcomes of CMV in organ transplant recipients result from both direct cytopathic and indirect immune-modulatory effects of CMV viral replication. The recognition of the negative effects of CMV in solid organ transplantation has resulted in the routine prophylaxis of organ recipients with antiviral nucleoside analogues. The appropriate duration of therapy is still controversial although guidelines do exist. The ability to assay an individual immune response to CMV should allow for tailored duration of therapy in the future.

Stem cells have an essential role in tissue homeostasis, repair, and regeneration of a tissue or an organ. Stem cells are immature cells having unlimited ability of self-renewal and capacity to differentiate into specialized cell types. Proper regulation of these dual properties is critical in animal development, growth control, and reproduction. Accumulating evidences suggest that stem cell behavior is regulated by both extracellular signals from the niche cells and intrinsic signal within stem cells. Using diverse model systems, tremendous work has been done to understand how niche control the stem cell self-renewal and differentiation. This review presents the progress made in stem cell niche field in germline and somatic stem cells in lower organism and mammals. The knowledge gained by studying the stem cells and its niches in diverse model organisms and the molecular mechanisms regulate their behavior are vital in understanding tissue homeostasis, regeneration, aging and cancer in humans.

The gastric mucosa and its glands show continuous bidirectional self-renewal via differentiation from stem and progenitor cells. Here, two types of gastric units, i.e., fundic and antral units, form delicate homeostatic systems. This review focuses on recent developments concerning the different types of gastric stem cells, the central function of parietal cells as organizing centres of fundic units, the stepwise differentiation of zymogenic cells via trans-differentiation of mucous neck cells, and unexpected differences between fundic and antral surface mucous cells. Within the last years, the central role of Sonic hedgehog (Shh) for correct self-renewal of fundic units has become much clearer. Furthermore, also the knowledge concerning the genesis of gastric cancer increased substantially. Here, chronic inflammation leads to dysregulated differentiation processes and finally to cancer. Remarkable progress has been made particularly concerning the genesis of two metaplastic cell lineages, i.e., the TFF2/spasmolytic polypeptide expressing metaplasia (SPEM) and intestinal metaplasia, which both arise in intestinal-type cancers in fundic units by dysregulated trans-differentiation of the zymogenic cell lineage. Additionally, Shh has been recognized as a target for inflammatory processes and an important player for innate immunity processes. Thus, stem cells, self-renewal, and gastric cancer are intimately linked.

The skin epithelium undergoes constant renewal, a process that is driven by stem cells (SCs) localising to the interfollicular epidermis and different regions of the hair follicle. Over the last years, tremendous progress has been made to unravel the physiological function of distinct stem and progenitor cell populations by using genetic lineage tracing in vivo, transplantation, clonogenicity approaches and live cell imaging. It turned out that these cell compartments constitute heterogeneous SC pools and that individual SCs respond differently to various signals sent by the microenvironment. Recent genetic manipulation experiments and elegant mouse models have shed light on the signalling pathways being crucial for self-renewal and lineage fate decisions during tissue homeostasis. Here, we summarise current concepts of SC function in mammalian skin and focus on the dynamic behaviour of SCs during morphogenesis and tissue regeneration of the skin epithelium. Clearly, understanding the cellular and molecular mechanisms of SC regulation and function during tissue homeostasis has enormous impact on our view of the pathogenesis of various skin diseases and will be beneficial for regenerative medicine. Recent experiments suggest an important role of tissue SCs in the process of skin tumour initiation and progression. For the future, the genuine challenge is to further dissect SC function in pathophysiological settings and to translate our knowledge to design novel efficient therapeutic strategies for treatment of cutaneous cancer.

After myocardial infarction, the lost healthy myocardium is replaced by non-contractile scar tissue which may lead to the development of heart failure and death. There is no curative therapy for the irreversible myocardial cell loss. This review will give an overview of the current options to restore the contractile force of the heart: the different stem cell sources as therapeutic agents in cardiac repair as well as more novel approaches like the activation of endogenous cell populations, the use of paracrine factors and engineered heart tissue.

Lung injuries that impact the alveolus, such as emphysema, pulmonary fibrosis, and acute lung injury, are costly and prevalent problems. Moreover, the extent of alveolar injury and impairment of gas exchange is strongly associated with prognosis and survival. Thus, mechanisms of repair and regeneration of the lung alveolar compartment have received mounting attention as newer approaches to the study of stem and progenitor cells in this region unfold. The role of type II alveolar epithelial as the sole source of type I (AECI) and II (AECII) alveolar epithelial cells following lung injury has been recently challenged; recently, investigators have described stemprogenitor cells that function like precursors to AECII either in vitro or in vivo, both in mice and humans. Techniques to explore selfrenewal and multipotency have been rigorously applied to these putative stem-progenitor cell populations and the data thus far is compelling. This review provides background to the study of alveolar regeneration with the aim to provide context to the recent discoveries of putative stem-progenitor cells that may contribute to this process.

Currently many efforts are being made to apply regenerative medicine to kidney diseases using several types of stem/progenitor cells, such as mesenchymal stem cells, renal stem/progenitor cells, embryonic stem cells and induced pluripotent stem cells. Stem cells have the ability to repair injured organs and ameliorate damaged function. The strategy for kidney tissue repair is the recruitment of stem cells and soluble reparative factors to the kidney to elicit tissue repair and the induction of dedifferentiation of resident renal cells. On the other hand, where renal structure is totally disrupted, absolute kidney organ regeneration is needed to rebuild a whole functional kidney. In this review, we describe current advances in stem cell research for kidney tissue repair and de novo organ regeneration.

Cell transplantation has been proposed as a means of replacing specific cell populations lost through neurodegenerative processes such as that seen in Parkinson's or Huntington's diseases. Improvement of the clinical symptoms has been observed in a number of Parkinson and Huntington's patients transplanted with freshly isolated fetal brain tissue but such restorative approach is greatly hampered by logistic and ethical concerns relative to the use of fetal tissue, in addition to potential side effects that remain to be controlled. In this context, stem cells that are capable of self-renewal and can differentiate into neurons, have received a great deal of interest, as demonstrated by the numerous studies based on the transplantation of neural stem/progenitor cells, embryonic stem cells or mesenchymal stem cells into animal models of Parkinson's or Huntington's diseases. More recently, the induction of pluripotent stem cells from somatic adult cells has raised a new hope for the treatment of neurodegenerative diseases. In the present article, we review the main experimental approaches to assess the efficiency of cell–based therapy for Parkinson's or Huntington's diseases, and discuss the recent advances in using stem cells to replace lost dopaminergic mesencephalic or striatal neurons. Characteristics of the different stem cells are extensively examined with a special attention to their ability of producing neurotrophic or immunosuppressive factors, as these may provide a favourable environment for brain tissue repair and long-term survival of transplanted cells in the central nervous system. Thus, stem cell therapy can be a valuable tool in regenerative medicine.

The evidence seems to be growing in favor of the stem cell theory of cancer with the emergence of studies demonstrating the parallel mechanisms of self renewing pathways in stem cells and particular subsets of cancer cells. The finding of leukemia stem cells and subsequently breast cancer stem cells (BCSC) further supports the concept. The importance of these findings lends itself to the selfrenewal properties of stem cells in addition to the survival characteristics of stem cells, mechanisms that will have to be overcome when creating treatment modalities. In particular, research has shown that stem cells and a specific type of stem cells, mesenchymal stem cells (MSC), have special drug effluxing properties and some interactions with particular cells of the immune system that may serve major roles in immunosuppresion and overall tumor cell survival. Furthermore, the recent discovery of epithelial to mesenchymal transition (EMT) has laid out a possible mechanism for tumor cells to lose particular phenotypic epithelial cell markers and gain phenotypic mesenchymal cell markers. This process is implicated in metastasis in addition to overall tumor survival and evasion of the immune system. This review examines the current understanding of how tumor cells evade the immune system, but will first explore stem cells, cancer stem cells, normal immune interaction with tumor cells, and EMT.

Glioblastoma multiforme (GBM) is the most common primary brain tumor and among the most lethal cancers. There is increasing evidence that cancer stem cells within GBMs, which are often referred to as glioblastoma stem cells (GSCs), play a critical role in tumor initiation and maintenance. Identification of novel markers for GSCs will lead to better targeting of GSCs which could have tremendous impact on treatment of GBMs. Cell surface markers are particularly suitable as therapeutic targets. Although several promising cell surface markers have successfully been used for enrichment of GSCs, their functional roles in maintenance of GSC properties as well as in GBM formation and development remain to be characterized. In this review, we primarily summarize recent advances in identification of GSC markers, with a particular focus on cell surface markers.

Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent and deadly cancer that has not shown improvements in survival rates for many years. Current treatments of HNSCC include surgical resection, radiotherapy, and chemotherapy, which are relatively ineffective for the management of recurrent or metastatic tumors. Cancer stem cells (CSC) within HNSCC offer an attractive therapeutic target for improving the survival rates for such cases, as eliminating the cells responsible for tumor initiation will theoretically prevent the onset of metastasis and recurrence. Since CSCs were initially isolated from HNSCC, there have been a handful of papers published that examine the potential of certain agents to selectively inhibit HNSCC CSCs, although a review of these papers has not yet been performed. Here we review the current literature for potential compounds or particles which have been proposed to selectively target the HNSCC CSC subpopulation. The various agents that have been tested so far include RNA interference, cell-based immunotherapy, antibodies, chemicals, microRNA precursors, and lentiviral microRNA vectors. Although many of these compounds showed considerable promise, few, if any, of the studies provided comprehensive evidence showing that the proposed agents were specific to CSCs and were considerably more effective than conventional therapy (radiation, cisplatin, etc). The proposed treatments in these studies require further investigation in these two regards, especially through rigorous in vivo experimentation, before they can be considered as true potential CSC inhibitors, let alone be considered for use in clinical trials.

The development of in vitro testing strategies for chemical and drug screening is a priority need in order to protect human health, to increase safety, to reduce the number of animals required for conventional testing methods and finally to meet the deadlines of current legislations. The aim of this work was to design an alternative testing method based on human embryonic stem cells for the detection of prenatal neural toxicity. For this purpose we have created a model based on the generation of neural rosettes, reproducing in vitro the gastrulation events recapitulating the formation of the neural tube in vivo. To validate the model we have exposed this complex cell system to increasing concentrations of valproic acid, a known teratogenic agent, to analyse the morphological and molecular changes induced by the toxicant. Specific assays were applied to discriminate between cytotoxicity and specific neural toxicity. Transcriptomic analysis was performed with a microarray Affimetrix platform and validated by quantitative real time RT-PCR for the expression of genes involved in early neural development, neural tube formation and neural cells migration, key biological processes in which the effect of valproic acid is most relevant. The results demonstrated that neural rosette cells respond to valproic acid exposure with molecular and morphological changes similar to those observed in vivo, indicating that this method represents a promising alternative test for the detection of human prenatal neural toxicity.

Salubrinal is a selective inhibitor of endoplasmic reticulum (ER) stress and affords remarkable protection to cardiomyocytes. By studying the structure–activity relationship (SAR) of salubrinal, it was found that modification of the quinoline ring terminus and thiourea unit could confer the compound PP1-24 with markedly enhanced cardioprotective activity (EC50 ≤ 0.3 μM) that is 50-fold more potent than salubrinal. Comparative molecular field analysis (CoMFA) was performed using the obtained biological data and resulted in a statistically significant CoMFA model with high predictive power (q2 = 0.741, r2 = 0.991).