Current Signal Transduction Therapy - Volume 6, Issue 3, 2011

Neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke and multiple sclerosis (MS) are caused by an extensive loss of neurons and glial cells into the brain. Regrettably, there are no effective treatments against any of these disorders, yet. Recently, cell replacement and gene transfer into the damaged brain have shown a high potential for the design of novel therapeutic strategies to treat a broad spectrum of human neurological diseases. This special issue is a timely compilation of comprehensive and concise reviews, which summarize the most important experimental and preclinical studies involving stem-cell-based and gene therapies against neurodegenerative diseases. All contributors are experts in specific fields and all of them discuss the benefits and potential pitfalls of stem-cell-based therapies in several neurological disorders. Because they were written using a simple language, these peer-reviewed contributions are suitable for novices and experts readers. This issue begins with a concise review that provides basic concepts and describes the cellular composition of the subventricular zone, the main niche of the neural stem cells in the adult brain. Additionally, this review also describes the signals involved in proliferation, survival, migration and differentiation of neural stem cells under physiological conditions. In an excellent review, Kasahara et al. explain the role of stem cells and the cell signals involved in the brain repair after stroke. As elegantly discussed by Kabatas and colleagues, these beneficial properties of stem cells are not exclusive for cerebral ischemia, but also appear to be useful in traumatic injuries. Increasing evidence indicates that stem cells play an important role in sustained tissue restoration and cellular homeostasis into the brain. This is a crucial property for the design of therapies against chronic neurodegenerative processes. In a landmark review, Rivera et al. comprehensively explain the cell signals that control mesenchymal and neural stem cells in myelination and remyelination of injured white matter. On the other hand, Mitrecic et al. nicely explicate recent data found against amyotrophic lateral sclerosis. Millan and Gonzalez-Castaneda conclude this special issue explaining the novel advances reached in stem-cell-based therapies in models of Parkinson's and Alzheimer's disease, respectively. In summary, growing evidence indicates that mesenchymal and neural stem cells are good candidates to establish stem cellbased therapies in neural disorders. Mature neurons and oligodendrocytes are efficiently generated from these multipotent cells. In parallel, extensive efforts to develop stem-cell transplantations have been successfully performed under experimental conditions. Nevertheless chemical mediators and signaling pathways involved in all these processes are to be fully elucidated, before these stem-cell-based therapies become a realistic clinical tool against neurodegenerative diseases.

Multiple sclerosis (MS) is a demyelinating immune-mediated disease of the central nervous system (CNS). It is the most common cause of acquired disability in young adults and affects over 2 Mio people worldwide. Current treatments target primarily the immune system, reduce the relapse rate and the formation of inflammatory lesions in the CNS, however with only temporary and limited success. Unfortunately, self-repair mechanisms of the CNS have been largely neglected in the past. The identification of neural and oligodendroglial progenitors in the brain and spinal cord, however, evoked the hypothesis that remyelination might be achieved through the activation of endogenous progenitors leading ultimately to functional recovery of the patient. Indeed, spontaneous remyelination is a common feature in MS, at least in the early phases of the disease, however, its levels and its qualities are apparently insufficient for a sustained endogenous functional repair. Here, we review the current knowledge on remyelination mechanisms and describe recent developments on molecular as well as on neural and mesenchymal stem cell therapies for MS treatment.

Neural stem cells (NSC) are cells that have the capacity to generate multiple types of differentiated brain cells. In conditions in which there is a loss of key functional cell groups, such as neurons, inducing or introducing neural stem cells to replace the function of those cells that were lost during the disease has the greatest potential therapeutic applications. Indeed, the achievement of one of the main objectives of various investigations is already on the horizon for some conditions, such as Alzheimer's disease. It is not known whether impaired neurogenesis contributes to neuronal depletion and cognitive dysfunction in Alzheimer's disease (AD). The results of the different investigations are controversial; some studies have found that neurogenesis is increased in AD brains, but others have not.

The subventricular zone (SVZ), lining the lateral ventricular system, is the largest germinal region in mammals. In there, neural stem cells express markers related to astroglial lineage that give rise to new neurons and oligodendrocytes in vivo. In the adult human brain, in vitro evidence has also shown that astrocytic cells isolated from the SVZ can generate new neurons and oligodendrocytes. These proliferative cells are strongly controlled by a number of signals and molecules that modulate, activate or repress the cell division, renewal, proliferation and fate of neural stem cells. In this review, we summarize the cellular composition of the adult human SVZ (hSVZ) and discuss the increasing evidence showing that some trophic modulators strongly control the function of neural stem cells in the SVZ.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity in the world. Unfortunately, no effective treatments are currently available for TBI. On the other hand, different types of stem cells have shown to selectively target injured brain and improve functional recovery. Moreover, recent data suggest that strategies regarding neurogenesis and angiogenesis following brain injuries may provide promising results. This paper aims to briefly review the current status and potential of using stem cells in the TBI.

Human fetal mesencephalic tissue can be successfully used in dopamine (DA) cell replacement therapy in Parkinson's disease (PD), nevertheless, further advances have been impeded due to limited tissue availability. Stem cell-based approaches have received much hype as potential treatments for neurodegenerative disorders, but have shown poor cell survival. The brains of three patients with Parkinson's disease who had undergone transplants of fetal tissue were examined postmortem and it was observed that some transplanted cells contained clumps of protein containing alpha-synuclein. Inducible pluripotent stem (iPS) cells derived from somatic cells and human embryonic stem cells, represent a novel renewable source of tissue precursors and therapeutic safety necessitate much more in-depth research before the initiation of human clinical trials.

Stem cells - based therapy is one of the most promising therapeutic approaches for amyotrophic lateral sclerosis (ALS), which is a fatal neurodegenerative disease without cure. This paper reviews the most intriguing pre-clinical and clinical studies and reports the current status of knowledge regarding ALS pathogenesis, confronting it with stem cell applications and their effects. Here we summarize various therapeutic approaches with respect to different sources of stem cells and diverse administration routes. Observed slow down of the disease progression and acceptable side effects emerge as the solid basis for optimism regarding the potential of the stem cell therapy for ALS.

Stroke is the leading cause of disability in developed countries, and investigations to identify ways to recover lost neurological function continue. The potential of stem cell therapy could be enormous, but current knowledge and techniques remain limited. In this review article, findings related to the therapeutic potential of acceleration of endogenous neurogenesis and neuronal stem cell transplantation are introduced. The therapeutic effects of acceleration of endogenous neurogenesis have been shown to be mild, but they improve neurological function significantly, and clinical trials are ongoing. In contrast, the potential of neural stem cell transplantation has been reported in many basic experiments, but current basic knowledge and techniques are likely to be insufficient to proceed to clinical trials. The possible missing elements for successful neuronal stem cell transplantation in patients with cerebral infarction are discussed.

Protein Kinase C isoforms (PKCs) are serine/threonine kinases that mediate multiple cellular functions and have been implicated in the patho-physiology of cancer, diabetes and cardiovascular diseases such as ischemia, cardiac hypertrophy, heart failure, and atherosclerosis. Blood components such as platelets contribute to thrombus formation resulting in stroke and myocardial infarction under patho-physiological conditions. PKCs mediate distinct platelet functional responses upon stimulation of different platelet receptors. Current research strategies employ the usage of PKC isoform-specific inhibitors to dissect their role in mediating platelet functional responses. This strategy has been complemented with studies in murine platelets lacking a specific PKC isoform. Furthermore, these studies have been extended to in vivo thrombosis animal models in order to correlate the in vitro observations to the formation of thrombus in vivo. It has been shown that PKCs play an important role in platelet secretion, aggregation and thrombus stabilization. In the current review, we discuss the role of various classes of PKCs in the complexity of signaling interplay in platelets, their implications to thrombosis, and also outline the possible therapeutic interventions.

The animal ribonucleases and plant nucleases are selective cytotoxic enzymes with several biological activities inclusively also with antitumorous effects. The first attention from animal researches is dated to 1938 year, meanwhile plant enzyme investigators awoke their attention in last time. The bovine pancreatic ribonuclease, after the first structurally studies, allured very soon the peoples with functionally interests. The results of studies directed to antitumor effect were firstly very weak. The latter isolated bovine seminal ribonuclease was more effective from this aspect. Also human pancreatic ribonuclease stimulated interest about its antitumor activity what was realized by its dimerization and other molecular studies. Ribonuclease inhibitors have been very limited substances in the cytotoxicity of antitumor effectivity. On the other side a conjugation of cytostatic enzymes with polymers enhanced the antitumor activity of them and lowered their toxicity. Plants as producers of new engineered pharmaceuticals are becoming a very attractive tool to improve human health. In last years the main attention from the plant antitumor effects begun to devote to plant ribonucleases and mainly nucleases I. These nucleases, major plant sugar non-specific endonucleases form rather heterogenous group of catalytically related enzymes. An important property that suggests intimate heterogeneity within the nuclease group is the specificity towards secondary structures of nucleic acids and the ability to cleave different homopolymers. Angiogenin, as RNase initiates vascularization of tumors and subsequent tumor growth. The new substances against angiogenin and its process angiogenesis are now in the centrum of antitumor-effort. The combination of these three main substances - ribonuclease, nucleases and antiangiogenins seems to be perspective for further studies. The preliminary results with some of them (bovine pancreatic RNase A, or bovine seminal BS-RNase with tomato recombinant nuclease and antiangiogenesis neamine, hyaluronidase, and melatonin is our first step.

The EGF and its receptor (EGFR) play an important role in the pathogenesis of different tumors. Gefitinib (Iressa) has been shown to suppress the activation of EGFR signaling required for cell survival and proliferation in nonsmall cell lung cancer (NSCLC) cell lines. We recently demonstrated that gefitinib-sensitive cells show efficient endocytosis of EGFR. In contrast, gefitinib-resistant cells showed internalized EGFR accumulation in the aggregated early endosomes that was revealed to be associated with SNX1, originally identified as a protein that interacts with EGFR. These results indicate an aberration in some steps of EGF-EGFR trafficking from the early endosomes to late endosomes/ lysosomes in the gefitinib-resistant cells. Here, we conducted the present study to investigate the relationship between EGF-stimulated pEGFR endocytosis and SNX1 trafficking via the endocytic pathway in the gefitinib-sensitive and gefitinib-resistant NSCLC cells by employing confocal immunofluorescence microscopy. We demonstrate that EGF stimulates efficient EGFR phosphorylation and the rapid endocytic delivery of pEGFR from the plasma membrane to early endosomes/late endosomes/lysosomes in a gefitinib-sensitive NSCLC cell line. Moreover, we made the novel observation that after EGF stimulation there is a rapid release of SNX1 from early endosomes in gefitinib-sensitive cells along with a concomitant time-dependent increase in nuclear SNX1. In contrast, following EGF-stimulation of gefitinibresistant cells, most SNX1 staining remained associated with aggregated early endosomes in which internalized pEGFR gradually accumulated instead of being trafficked to late endosomes/lysosomes, suggesting that the EGF-dependent nuclear translocation mechanism of SNX1 is significantly perturbed. Moreover, this translocation of SNX1 from early endosomes in gefitinib-sensitive cells was completely abolished by latrunculin B treatment, indicating that the actin cytoskeleton may mediate the EGF-stimulated nuclear translocation of SNX1. Collectively, we postulate that SNX1 is involved in the negative regulation of EGF-dependent EGFR trafficking out of early endosomes to late endosomes/ lysosomes, and suggest that impairment of the nuclear trafficking machinery of SNX1 regulating pEGFR endocytosis might perturb pEGFR release from early endosomes, which subsequently leads to the acquisition of gefitinib-resistance in NSCLC cell lines.

In this work, we computationally identified the most detrimental missense mutations of ABL tyrosine kinase in Chronic Myelogenous Leukemia (CML) and analyzed the drug resistance from these detrimental missense mutations. Out of 45 missense mutations, 20 variants were commonly found less stable, deleterious and damaging by I-Mutant2.0, SIFT and PolyPhen programs respectively. Subsequently, we performed modeling of these 20 variants to understand their change in conformations with respect to native ABL tyrosine kinase by computing their RMSD (Root Mean Square Deviation). Further, the native and 20 mutants were docked with the drug ‘imatinib’ to find out the drug resistance of these detrimental missense mutations. Among the 20 mutants, we found by docking studies that 12 mutants, namely M244V, Q252H, Y253H, K285N, T315I, F317L, F317I, S349L, M351T, E355G, S417Y and W430L had less binding affinity with imatinib than the native type. Finally, we analyzed that the loss of binding affinity of these 12 mutants were due to altered flexibility in their binding amino acids with imatinib as compared with native type by normal mode analysis. In our work, we found the novel data that majority of the drug binding amino acids in those 12 mutants had encountered the loss of flexibility which could be the theoretical basis for the cause of drug resistance.

Signalling from receptor tyrosine kinases is presumably the most investigated pathway so far and myriad of protein components and respective interactions involved have been outlined. Considerably, disconcerted receptor tyrosine kinase signalling has been implicated in the generation and maintenance of many different human diseases. The two crucial interlinked axes in receptor tyrosine kinase signalling have received immense attention as therapeutic targets. One contains the Ras activated Raf kinases and their object kinase cascade, the other involves phosphoinositide 3-kinase (PI3K) and downstream targets like the protein kinase Akt (also known as protein kinase B). The PI3K pathway regulates various cellular functions such as proliferation, survival, migration and metabolism. Small molecule PI3K inhibitors with isoenzyme selectivity have been developed in growing number and used as tools to elucidate the isoenzyme specific functions. The pharmacological inhibitors assayed for potentials as therapeutic agents in the treatment of diseases as diverse as cancer, leukaemia, thrombosis and allergic response in different model systems presented promising and also some unexpected results.

The malignant brain tumour, glioblastoma, is invariably fatal with an average survival of 8-11 months (recent pharmacology has increased the median survival to 15, and rarely to 18 months). Different growth factors participate in the malignant development of the brain, especially IGF-1, EGF, TGF-beta and VEGF. Among the strategies applied to target and arrest the expression of growth factors, their receptors (tyrosine kinase) and down stream signalling pathway elements (i.e. PKC, Bcl-2, glycogen synthase) involved in cancer processes, the use of different inhibitors and especially of antisense technique has been among the leading technology proposed. Recent clinical results of glioblastomas are especially promising in situations in which antisense was used either as gene therapy (antisense anti TGF beta oligodeoxynucleotides), or as cellular gene therapy (transfection with antisense anti IGFI expression vector), following a classical surgery, radio- and chemotherapy. Using anti - IGF-I approach, median survival in glioblastoma patients has reached 21 months. The immune anti-tumour response in treated patients was confirmed by an increase of CD8+ T level in peripheral blood lymphocytes.

Some of Alzheimer's syndromes are investigated and it is demonstrated that principal reason of them is brain shrinking. In this situation size of holes in brain is smaller than natural state. Natural frequency of holes is calculated for healthy and Alzheimer brains and it is demonstrated that an applied ultrasound wave with this frequency can resonate oscillation of holes diameter and consequently can restore health of brain. Because novelty of this method, it is applied to healthy brain of sheep and this theoretical method is approved.

This review summarizes the key role of Toll-Like Receptor (TLRs) molecules for igniting the immune system. Activated by a broad spectrum of pathogens, cytokines or other specific molecules, TLRs trigger innate immune responses. Published data demonstrate that the targeting and suppression of TLRs and TLR-related proteins with particular inhibitors may provide pivotal treatments for patients with cancer, asthma, sepsis, Crohn's disease and thrombosis. Many drugs that target cytokines act in the late phases of the activated pathways, after the final peptides, proteins or glycoproteins are formed in the cell environment. TLR activity occurs in the early activation of cellular pathways; consequently inhibiting them might be most beneficial in the treatment of human diseases.

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