Current Molecular Medicine

ISSN: 1566-5240

Current Molecular Medicine
Volume 7, Number 7, November 2007

Contents

Nanotechnology as an Adjunct Tool for Transplanting Engineered Cells and Tissues Pp. 609-618
Cesar V. Borlongan, Tadashi Masuda, Tiffany A. Walker, Mina Maki, Koichi Hara, Takao Yasuhara, Noriyuki Matsukawa and Dwaine F. Emerich
[Abstract]


Nuclear Factor-Kappa B: From Clone to Clinic Pp. 619-637
Kwang Seok Ahn, Gautam Sethi and Bharat B. Aggarwal
[Abstract]


The Ability of Melatonin to Counteract Lipid Peroxidation in Biological Membranes Pp. 638-649
Angel Catalá
[Abstract]


DJ-1: A New Comer in Parkinson’s Disease Pathology Pp. 650-657
Cristine Alves da Costa
[Abstract]


γδ T Cells and Dendritic Cells: Close Partners and Biological Adjuvants for New Therapies Pp. 658-673
Angelo Martino and Fabrizio Poccia
[Abstract]


Oxidative Stress and the JNK Pathway are Involved in the Development of Type 1 and Type 2 Diabetes Pp. 674-686
Hideaki Kaneto, Taka-aki Matsuoka, Naoto Katakami, Dan Kawamori, Takeshi Miyatsuka, Kazutomi Yoshiuchi, Tetsuyuki Yasuda, Ken’ya Sakamoto, Yoshimitsu Yamasaki and Munehide Matsuhisa
[Abstract]


Molecular and Cellular Mechanisms for Alzheimer's Disease: Understanding APP Metabolism Pp. 687-696
Yun-wu Zhang and Huaxi Xu
[Abstract]




Abstracts


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Nanotechnology as an Adjunct Tool for Transplanting Engineered Cells and Tissues
Cesar V. Borlongan, Tadashi Masuda, Tiffany A. Walker, Mina Maki, Koichi Hara, Takao Yasuhara, Noriyuki Matsukawa and Dwaine F. Emerich

Laboratory and clinical studies have provided evidence of feasibility, safety and efficacy of cell transplantation to treat a wide variety of diseases characterized by tissue and cell dysfunction ranging from diabetes to spinal cord injury. However, major hurdles remain and limit pursuing large clinical trials, including the availability of a universal cell source that can be differentiated into specific cellular phenotypes, methods to protect the transplanted allogeneic or xenogeneic cells from rejection by the host immune system, techniques to enhance cellular integration of the transplant within the host tissue, strategies for in vivo detection and monitoring of the cellular implants, and new techniques to deliver genes to cells without eliciting a host immune response. Finding ways to circumvent these obstacles will benefit considerably from being able to understand, visualize, and control cellular interactions at a sub-micron level. Cutting-edge discoveries in the multidisciplinary field of nanotechnology have provided us a platform to manipulate materials, tissues, cells, and DNA at the level of and within the individual cell. Clearly, the scientific innovations achieved with nanotechnology are a welcome strategy for enhancing the generally encouraging results already achieved in cell transplantation. This review article discusses recent progress in the field of nanotechnology as a tool for tissue engineering, gene therapy, cell immunoisolation, and cell imaging, highlighting its direct applications in cell transplantation therapy.


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Nuclear Factor-Kappa B: From Clone to Clinic
Kwang Seok Ahn, Gautam Sethi and Bharat B. Aggarwal

Nuclear transcription factor κB (NF-κB) was first discovered in 1986 in the nucleus of the B cell as an enhancer in the κ immunoglobulin chain. However, this factor has identified in the cytoplasm in the resting state. When activated in response to inflammatory stimuli, carcinogens, stress, ionizing radiation, and growth factors; NF-κB translocates to the nucleus where it upregulates the expression of over 400 different gene products linked with inflammation, cell survival, proliferation, invasion, and angiogenesis. The activation of NF-κB has now been linked with a variety of inflammatory diseases, including cancer and pulmonary, autoimmune, skin, neurodegenerative, and cardiovascular disorders. Indeed, constitutive NF-κB activation frequently correlates with the proliferation, survival, chemoresistance, radioresistance, and progression of various cancers. Hence, NF-κB has both diagnostic and prognostic applications. In addition, pharmaceutical companies are aggressively pursuing development of inhibitors of NF-κB with therapeutic potential. Thus within last decades this transcription factor, discovered serendipitously, has moved from “clone to clinic”.


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The Ability of Melatonin to Counteract Lipid Peroxidation in Biological Membranes
Angel Catalá

This paper reviews recent data relevant to the antioxidant effects of melatonin with special emphasis on the changes produced in polyunsaturated fatty acids located in the phospholipids of biological membranes. The onset of lipid peroxidation within cellular membranes is associated with changes in their physicochemical properties and with the impairment of protein functions located in the membrane environment. All cellular membranes are especially vulnerable to oxidation due to their high concentration of polyunsaturated fatty acids. These processes combine to produce changes in the biophysical properties of membranes that can have profound effects on the activity of membrane-bound proteins. This review deals with aspects for lipid per-oxidation of biological membranes in general, but with some emphasis on changes of polyunsaturated fatty acids, which arise most prominently in membranes and have been studied extensively in our laboratory. The article provides current information on the effect of melatonin on biological membranes, changes in fluidity, fatty acid composition and lipid-protein modifications during the lipid peroxidation process of photoreceptor membranes and modulation of gene expression by the hormone and its preventive effects on adriamycin-induced lipid peroxidation in rat liver. Simple model systems have often been employed to measure the activity of antioxidants. Although such studies are important and essential to understand the mechanisms and kinetics of antioxidant action, it should be noted that the results of simple in vitro model experiments cannot be directly extrapolated to in vivo systems. For example, the antioxidant capacity of melatonin, one of the important physiological lipophilic antioxidants, in solution of pure triglycerides enriched in ω-3 polyunsaturated fatty acids is considerably different from that in subcellular membranes.


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DJ-1: A New Comer in Parkinson’s Disease Pathology
Cristine Alves da Costa

Parkinson’s disease (PD) is a movement disorder of high prevalence in the elderly. It is characterized by a loss of dopaminergic neurons and the presence of intracytoplasmic inclusions named Lewy bodies. To date six familial PD-associated proteins have been identified so far. Some of them are implicated in the development of either autosomal dominant (α-synuclein and LRRK2 (leucine-rich repeat kinase 2/dardarin) or early-onset recessive (parkin, DJ-1, PINK1 (PTEN-induced kinase-1) and ATP13A2) PD forms. A number of genetic studies have shown that 50% of the recessive forms are linked to mutations on parkin gene, followed by PINK1 (8-15%) and DJ-1 (1%). The purpose of this review is to provide an overview of the emerging data on the cellular and molecular biology of DJ-1. DJ-1 is a ubiquitous protein that was first described as an oncogene. Nevertheless, after its association to monogenic PD a number considerable data aiming at understanding its implication in the physiopathology of PD was produced. This review will describe the main advances concerning the function of DJ-1. A considerable progress that was only possible due to a better understanding of DJ-1 structure, genetics, distribution and development of in vivo models. All these points along with the description of recent data showing the interaction of DJ-1 with other PD-associated proteins will be given.


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γδ T Cells and Dendritic Cells: Close Partners and Biological Adjuvants for New Therapies
Angelo Martino and Fabrizio Poccia

The knowledge of several signals influencing Dendritic Cell (DC) functions is crucial to manipulate the immune system for new vaccination therapies. Our recent findings provide a new model of intervention on DC system suggesting novel therapeutic implications. T, NK, and γδ T cell stimuli may enhance DC maturation, Th polarization and trigger the adaptive immune response. Regulatory effects of γδ T cells on inflammation and immune responses may be mediated by their interaction with DCs and they are analyzed in the last years in humans and mice. In humans, Vγ9Vδ2 T cells represent the most part of circulating γδ T cells and are activated by non-peptidic molecules derived from different microorganisms or abnormal metabolic routes. They share both NK-like and effector/memory T cell features, and among these the possibility to interact with DCs. Co-culture of immature DCs with activated Vγ9Vδ2 T cells allows DCs to acquire features of mature DCs complementing the migratory activity, up-regulating the chemokine receptors, and antigen presentation. Similarly to the NK-derived signals, DC activation is mostly mediated by soluble factors secreted by γδ T cells.

Many non-peptidic molecules including nitrogen-containing bisphosphonates and pyrophosphomonoester drugs stimulate the activity of Vγ9Vδ2 T cells in vitro and in vivo. The relatively low in vivo toxicity of many of these drugs makes possible novel vaccine and immune-based strategies, through DCs, for infectious and neo-plastic diseases.


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Oxidative Stress and the JNK Pathway are Involved in the Development of Type 1 and Type 2 Diabetes
Hideaki Kaneto, Taka-aki Matsuoka, Naoto Katakami, Dan Kawamori, Takeshi Miyatsuka, Kazutomi Yoshiuchi, Tetsuyuki Yasuda, Ken’ya Sakamoto, Yoshimitsu Yamasaki and Munehide Matsuhisa

Failure of pancreatic β-cells is the common characteristic of type 1 and type 2 diabetes. Type 1 diabetes mellitus is induced by destruction of pancreatic β-cells which is mediated by an autoimmune mechanism and consequent inflammatory process. Various inflammatory cytokines and oxidative stress are produced during this process, which has been proposed to play an important role in mediating β-cell destruction. The JNK pathway is also activated by such cytokines and oxidative stress, and is involved in β-cell destruction. Type 2 diabetes is the most prevalent and serious metabolic disease, and β-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Under diabetic conditions, chronic hyperglycemia gradually deteriorates β-cell function and aggravates insulin resistance. This process is called “glucose toxicity”. Under such conditions, oxidative stress is provoked and the JNK pathway is activated, which is likely involved in pancreatic β-cells dysfunction and insulin resistance. In addition, oxidative stress and activation of the JNK pathway are also involved in the progression of atherosclerosis which is often observed under diabetic conditions. Taken together, it is likely that oxidative stress and subsequent activation of the JNK pathway are involved in the pathogenesis of type 1 and type 2 diabetes.


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Molecular and Cellular Mechanisms for Alzheimer's Disease: Understanding APP Metabolism
Yun-wu Zhang and Huaxi Xu

Alzheimer’s disease (AD) is the most common neurodegenerative disease associated with aging. One important pathologic feature of AD is the formation of extracellular senile plaques in the brain, whose major components are small peptides called β-amyloid (Aβ) that are derived from β-amyloid precursor protein (APP) through sequential cleavages by β-secretase and γ-secretase. Because of the critical role of Aβ in the pathogenesis of AD, unraveling the cellular and molecular events underlying APP/Aβ metabolism has been and remains, of paramount importance to AD research. In this article we will focus on the regulation of APP metabolism leading to Aβ generation. We will review current knowledge of the secretases (α-, β-, and γ-secretases) involved in APP processing and various molecular and cellular mechanisms underlying intracellular trafficking of APP, which is a highly regulated process and whose disturbance has direct impacts on the production of Aβ.