Current Molecular Medicine - Volume 12, Issue 10, 2012

FTY720 is a recently approved first line therapy for relapsing forms of multiple sclerosis. In this context, FTY720 is a pro-drug, with its anti-multiple sclerosis, immunosuppressive effects largely elicited following its phosphorylation by sphingosine kinase 2 and subsequent modulation of G protein-coupled sphingosine 1-phosphate (S1P) receptor 1 that induces lymphopenia by altering lymphocyte trafficking. A number of other biological effects of FTY720 have, however, been described, including considerable evidence that this drug also has anti-cancer properties. These other effects of FTY720 are independent of S1P receptors, and appear facilitated by modulation of a range of other recently described protein targets by nonphosphorylated FTY720. Here, we review the direct targets of FTY720 that contribute to its anti-cancer properties. We also discuss other recently described protein effectors that, in combination with S1P receptors, appear to contribute to its immunosuppressive effects.

Tissue remodeling is critical during development and wound healing. It also characterizes a number of pathologic conditions, including chronic inflammation, fibrosis and cancer. It is well appreciated that reactive stromal cells play critical roles in these settings. However, understanding of the mechanisms involved in the differentiation of reactive stromal cells and their biologic activities has been hampered by the fact that they are generated from diverse progenitors, and by their phenotypic and function heterogeneity. Furthermore, molecular markers that are expressed by all reactive stromal cells and that distinguish them from all other cell types have been lacking. Fibroblast activation protein (FAP) is a serine protease that was originally discovered as a cell surface protein expressed on astrocytomas and sarcomas. Over the last two decades, FAP has attracted increasing attention as a selective marker of carcinoma-associated fibroblasts (CAFs) and more broadly, of activated fibroblasts in tissues undergoing remodeling of their extracellular matrix (ECM) due to chronic inflammation, fibrosis or wound healing. Herein we review the evidence that FAP is indeed a robust and selective marker for reactive mesenchymal stromal cells associated with pathophysiologic tissue remodeling. We also review recent insights obtained using FAP as a tool to define the relationship between subpopulations of reactive stromal cells in various settings of tissue remodeling. Furthermore, we review recent genetic and pharmacologic data indicating that FAP and FAP-expressing cells play important roles in such conditions. Finally, we discuss the potential risks and therapeutic benefits of targeting FAP and FAP-expressing cells, as well as approaches to do so.

Honokiol (3',5-di-(2-propenyl)-1,1'-biphenyl-2,4'-diol) is a bioactive natural product derived from Magnolia spp. Recent studies have demonstrated anti-inflammatory, anti-angiogenic, anti-oxidative and anticancer properties of honokiol in vitro and in preclinical models. Honokiol targets multiple signaling pathways including nuclear factor kappa B (NF-κB), signal transducers and activator of transcription 3 (STAT3), epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (m-TOR), which have great relevance during cancer initiation and progression. Furthermore, pharmacokinetic profile of honokiol has revealed a desirable spectrum of bioavailability after intravenous administration in animal models, thus making it a suitable agent for clinical trials. In this review, we discuss recent data describing the molecular targets of honokiol and its anti-cancer activities against various malignancies in pre-clinical models. Evaluation of honokiol in clinical trials will be the next step towards its possible human applications.

The olfactory system is unique in many respects—two of which include the process of adult neurogenesis which continually supplies it with newborn neurons, and the fact that neurodegenerative diseases are often accompanied by a loss of smell. A link between these two phenomena has been hypothesized, but recent evidence for the lack of robust adult neurogenesis in the human olfactory system calls into question this hypothesis. Nevertheless, model organisms continue to play a critical role in the exploration of neurodegenerative disease. In part one of this review we discuss the most promising recent technological advancements for studying adult neurogenesis in the murine olfactory system. Part two continues by looking at emerging evidence related to adult neurogenesis in neurodegenerative disease studied in model organisms and the differences between animal and human olfactory system adult neurogenesis. Hopefully, the careful application of advanced research methods to the study of neurodegenerative disease in model organisms, while taking into account the recently reported differences between the human and model organism olfactory system, will lead to a better understanding of the reasons for the susceptibility of olfaction to disease.

Type 1 diabetes mellitus (T1DM) is a T cell-mediated autoimmune disease resulting in islet β cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. T1DM has classically been attributed to the pathogenic actions of auto-reactive effector T cells(Teffs) on the β cell. Recent literature now suggests that a failure of a second T cell subtype, known as regulatory T cells (Tregs), plays a critical role in the development of T1DM. During immune homeostasis, Tregs counterbalance the actions of autoreactive Teff cells, thereby participating in peripheral tolerance. An imbalance in the activity between Teff and Tregs may be crucial in the breakdown of peripheral tolerance, leading to the development of T1DM. In this review, we summarize our current understanding of Treg function in health and in T1DM, and examine the effect of experimental therapies for T1DM on Treg cell number and function in both mice and humans.

Cellular repressor of E1A-stimulated genes (CREG), a novel cellular protein, was discovered in 1998. Accumulating evidence, mainly from our laboratory, has suggested that CREG plays critical roles in reducing neointimal hyperplasia, maintaining vascular homeostasis, and promoting endothelial restoration. The study of CREG has the potential to offer new insights into both prevention and treatment of proliferative vascular disease, and will help us understand the processes of vascular repair after injury. It will also contribute to the development of new therapeutic strategies and devices, such as anti-in-stent restenosis stents. The present review summarizes our research on the molecular identity of CREG, and reviews the biological activities of CREG in regulating cell differentiation, proliferation, migration, and apoptosis of vascular smooth muscle cells and endothelial cells.

Evidence shows that artificially lowering body and brain temperature can significantly reduce the deleterious effects of brain injury in both newborns and adults. Although the benefits of therapeutic hypothermia have long been known and applied clinically, the underlying molecular mechanisms have yet to be elucidated. Hypoxic-ischemic brain injury and traumatic brain injury both trigger a series of biochemical and molecular events that cause additional brain insult. Induction of therapeutic hypothermia seems to ameliorate the molecular cascade that culminates in neuronal damage. Hypothermia attenuates the toxicity produced by the initial injury that would normally produce reactive oxygen species, neurotransmitters, inflammatory mediators, and apoptosis. Experiments have been performed on various depths and levels of hypothermia to explore neuroprotection. This review summarizes what is currently known about the beneficial effects of therapeutic hypothermia in experimental models of neonatal hypoxic-ischemic brain injury and traumatic brain injury, and explores the molecular mechanisms that could become the targets of novel therapies. In addition, this review summarizes the clinical implications of therapeutic hypothermia in newborn hypoxic-ischemic encephalopathy and adult traumatic brain injury.

Pancreatic β-cell death of various types has diverse and important roles in the pathogenesis of both type 1 (T1D) and type 2 (T2D) diabetes. The most widely recognized types of β-cell death in diabetes are apoptosis (type 1 programmed cell death) and necrosis. Apoptosis of β-cells is the key and final step in the development of T1D and contributes to β-cell failure or dysfunction in T2D. In the course of natural T1D, apoptotic β-cells undergoing secondary necrosis probably due to their defective clearance by phagocytes, may be involved in the initiation and development of the disease. Recently, autophagy (type 2 programmed cell death) is proposed as a third type of cell death and is being recognized as having certain roles in the prevention and execution of β-cell death, depending on the cellular context. Moreover, as dying β-cells are routinely exposed to the immune system, β-cell death could also affect the development of diabetes through regulation of inflammation or immune response. In this review, we describe the role of various types of pancreatic β-cell death in the development of T1D and T2D. We also discuss the role of dying β-cells in the control of inflammation which contributes to the pathogenesis of diabetes.

Parkinson's disease (PD) is an age-related and the second most common neurodegenerative disorder beyond Alzheimer's disease. A neuropathological hallmark of PD is a prominent loss of dopaminergic neurons in the substantia nigra projecting into the caudate and putamen. Oral administration of L-dopa and/or dopamine agonists ameliorates cardinal motor symptoms of PD. However, an intermittent and long-term treatment with L-dopa frequently induces adverse side effects such as motor fluctuations and dyskinesia. As alternative therapeutic strategies, the following four approaches are currently under evaluation for clinical gene therapy trials in PD; 1) recombinant adeno-associated virus 2 system encoding aromatic L-amino acid decarboxylase (AADC), 2) glutamic acid decarboxylase (GAD) and 3) Neurturin, and 4) equine infectious anemia virus-based lentiviral system encoding AADC, tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) in a single transcriptional unit. GAD and Neurturin have been assessed in double blind placebocontrolled phase II studies; GAD showed a significant improvement in motor function, and Neurturin, although it failed to show significant effects at 12 months post-treatment, exhibited promising outcomes in additional examinations at 18 months. The other two approaches also represented significant effects in phase I or I/II studies. Adverse side effects due to surgery have not been observed. Here, we review preclinical and clinical trials encouraging further investigations of curative treatment for the patients suffering from PD.

Recent studies have demonstrated that mammalian homologues of Drosophila transient receptor potential (TRP) channels are widely expressed in human platelets. Occupation of G protein-coupled receptors by agonists results in activation of these channels, which results in Na+ and Ca2+ entry. Canonical or classic TRP (TRPC) family members have been reported to associate with different Ca2+-handling proteins, including the type II inositol 1,4,5-trisphosphate receptor, the endoplasmic reticulum Ca2+ sensor STIM1 (STromal Interaction Molecule-1) or the Ca2+ permeable channel Orai1. The dynamic interaction of TRPC channels with the above mentioned proteins has been found to be important for both store-operated and capacitative Ca2+ entry, as well as for non-capacitative Ca2+ influx. The former is a major mechanism for Ca2+ entry in human platelets. This mechanism, activated by a reduction in the concentration of free Ca2+ in the intracellular stores, results in the formation of signaling complexes involving STIM proteins, Orai1, Orai2, TRPC1 and TRPC6. There is a growing body of evidence supporting that Ca2+ signaling dysfunction plays an important role in the pathogenesis of several platelet-linked disorders, including those associated to type 2 diabetes mellitus. Abnormal Ca2+ signals in response to physiological agonists have been associated to platelet hyperactivity. The expression of several TRPCs, STIM1 and Orai1, as well as their interaction, has been reported to be altered in platelets from type 2 diabetic patients, which results in attenuated capacitative Ca2+ entry but enhanced non-capacitative Ca2+ influx; thus suggesting a role for Ca2+ handling proteins, including TRPs, in the pathomechanism of diabetic complications.

Allergic diseases are major diseases involving approximately 22% of world population. In recent years, accumulated evidence suggests that apart from IgE, allergens may provoke immediate allergic reactions via other pathways such as IgG, toll like receptor (TLR) dependent ones. In addition, large numbers of low molecular weight molecules (LMWM) such as sphingosine-1-phosphate and iodinated contrast agents have been observed to cause allergy. Therefore, the current definition of allergy, a group of IgE mediated diseases appears difficult to cover all allergic reactions. Since even IgE dependent allergic reactions are carried out through activation of mast cells and basophils, and all allergens mentioned above can activate these cells, we hypothesize that allergic reactions are mast cell and basophil mediated inflammatory process as it is the activated mast cells and basophils that initiate the pathological process of the immediate allergic reactions, whereas IgE only serves as one of the activators of these cells.

Human amnion-derived cells possess great potential for the repair of human neural disorders, and recent studies have broadened the spectrum for applications because they exhibit the characteristics of multipotent stem cells. These cells express embryonic stem cell markers such as Oct4, Nanog, Sox2, SSEA-3, SSEA-4 and Rex1, and can differentiate into multiple primary germ layers both in vitro and in vivo. Moreover, induced pluripotent stem cells have been generated from amnion-derived cells by virus-mediated delivery of three or four pluripotency-relating transcription factors or by the introduction of only one transcription factor with electroporation. Because human amnion-derived cells are readily available, less likely to contain genetic aberrations and can be reprogrammed earlier and more efficiently than differentiated cells, they can be ideal resources as the donor pluripotent stem cells for therapeutic purposes. We discuss here the highlights of recent studies and potential applications of human amnion-derived multipotent stem cells to stem cell biology as well as to regenerative medicine in the field of aging, heart disease, diabetes and neural disorders.

Spider venom is a large pharmacological repertoire containing many biologically active peptides, which may have a potent therapeutic implication. Here we investigated a peptide toxin, named lycosin-I, isolated from the venom of the spider Lycosa singoriensis. In contrast to most spider peptide toxins adopting inhibitor cystine knot (ICK) motif, lycosin-I shows a linear amphipathic alpha-helical conformation, common to α-helical host defense peptides. Lycosin-I displays strong ability to inhibit cancer cell growth in vitro and can effectively suppresses tumor growth in vivo. Mechanistically, it activates the mitochondrial death pathway to sensitize cancer cells for apoptosis, as well as up-regulates p27 to inhibit cell proliferation. Taken together, our results provide the first evidence that a spider toxin can effectively suppress tumorigenesis through activation of dual signaling pathways. In addition, lycosin-I may be a useful structural lead for the development of novel anticancer drugs.

Protein serine/threonine phosphatase-1 (PP-1) is one of the key enzymes responsible for dephosphorylation in vertebrates. Protein dephosphorylation via PP-1 is implicated in many different biological processes including gene expression, cell cycle control, transformation, neuronal transmission, apoptosis, autophage and senescence. However, whether PP-1 directly controls animal development remains to be investigated. Here, we present direct evidence to show that PP-1 plays an essential role in regulating eye development of vertebrates. Using goldfish as a model system, we have shown the following novel results. First, inhibition of PP-1 activity leads to death of a majority of the treated embryos, and the survived embryos displayed severe phenotype in the eye. Second, knockdown of each catalytic subunit of PP-1 with morpholino oligomers leads to partial (PP-lα knockdown) or complete (PP-lβ or PP-lγ knockdown) death of the injected embryos. The survived embryos from PP-1α knockdown displayed clear retardation in lens differentiation. Finally, overexpression of each subunit of PP-1 also causes death of majority of the injected embryos and leads to abnormal development of goldfish eye. Mechanistically, Pax-6 is one of the major downstream targets mediating the effects of PP-1 function since the eye phenotype in Pax-6 knockdown fish is similar to that derived from overexpression of PP-1. Together, our results for the first time provide direct evidence that protein phosphatase-1 plays a key role in governing normal eye formation during goldfish development.

As an essential component of eukaryotic cells, the nuclear envelope (NE) plays a crucial role in many physiological processes. At present, a few membrane proteins from NE have been functionally characterized. To determine whether the inner nuclear membrane (INM) protein Nurim is expressed in cancer cells with evidence of apoptosis, we identified three isoforms of this protein that are specific for human testicular seminoma and are generated by alternative splicing. We observed that Nurim is expressed in a broad range of cancer types and that its expression level is correlated with a higher tumor grade. Biochemical analysis showed that Nurim b, like a, is tightly bound to the nuclear envelope. Furthermore, knockdown using miR-Nurim resulted in an abnormal shape change of the nuclear envelope. Notably, Nurim knockdown obviously increased apoptosis induced by ultraviolet in HeLa cells. Together, these findings implicate that the INM protein Nurim plays an important role in the suppression of apoptosis.