Current Pharmaceutical Design - Volume 17, Issue 22, 2011

It is generally accepted that ROS is major cause of life style-dependent diseases such as cancer, stroke and many other serious diseases. So far they were treated individually by various kinds of drugs specially designed for each symptom, but these approaches must be changed innovatively. Generally, ROS is generated intracellularly when mitochondria is producing ATP, while it is also generated extracellularly by the stimulation of ultraviolet light, electro-magnetic waves (heat), ultra-sound and radiations. Consequently, ageing may be one of the consequences of these ROS-induced oxidative stresses. Though there are many antioxidants, one of the most direct approach to remove ROS from animal body is to apply reducing gas such as H2, H2S and CO, now regarded as medical gases. Especially H2 gas dissolving in water (H2 water) could be widely used as a reducing reagent [1], which was found to be very effective for a number of diseases. Not only as a reducing reagent, but molecular mechanisms for ROSresistance of medical gases are also proposed [2]. Lithium (Li) is involved in glucose metabolism via cyclic AMP (cAMP)-dependent kinase (PKA). Although it was already known that Li inhibited phosphoinositide (PI) turn-over, but recently Li was found to be incorporated with the central nervous system (CNS) disorder and diabetes via glycogen synthase kinase 3. It is, therefore, reasonable to study relationships between Li and ROS-induced CNS diseases [3]. It is our dream to find out key protein controlling senescense. So many attempts were carried out to find out the most effective molecules for longevity such as hydrophilic scavengers, enzymatic antioxidants, lipophilic scavengers, repair mechanism. A new approach is proposed here that chromatin-remodeling factors may be important players in the senescence program [4]. The most orthodox approach, however, for the molecular mechanism for senescence is to analyze ROS signaling network using ultra-long-lived animals. Naked mole rat (NMR) may be an excellent model animal, because they survive for 30 years without cancer. It has no pain sensing system, presumably reducing stresses to a great extent. If cancer and stress are representative symbols for aging-associated phenomena, study with NMR in detail will give us quite a new aspect for aging mechanism [5]. It has been established that formation of ROS may occur during the interaction of animal cells with nanoparticles. Furthermore, some types of nanoparticles are sensitive to light and produce singlet oxygen and super oxide as well. Although there is no direct evidence so far, interaction between mitochondria and nanoparticle was expected to affect electron flow which may cause dysfunction of intracellular Ca2+ concentration. In this issue, two reviews describe about nanoparticle as drug carrier. Above all the metallodendrimer is the most attractive, because it has highly branched structure and functionally tunable peripheral effects. Therefore this type of nanoparticle is highly applicable to many fields, such as biomimetic catalysis, imaging contrast agents and biomedical sensors [6]. The magnetic sensitive nanoparticle (MNPs) is another attractive characteristic of nanoparticles, which will be applicable for magnetic resonance imaging diagnosis, drug/gene carriers for different kind of therapeutic agents, tissue repair, hyperthermia, immunoassay and cell separation and/or sensing. In this issue attention was focused on how to synthesize better MNPs for ferrying them to interested areas. Especially DNA-targeting delivery was extensively reviewed [7].....

Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and the aging process. Acute oxidative stress directly causes serious damage to tissues. Despite the clinical importance of oxidative damage, antioxidants have been of limited therapeutic success. We have proposed that molecular hydrogen (H2) has potential as a “novel” antioxidant in preventive and therapeutic applications [Ohsawa et al., Nat Med. 2007: 13; 688-94]. H2 has a number of advantages as a potential antioxidant: H2 rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect reactive oxygen species (ROS) that function in cell signaling, thereby, there should be little adverse effects of consuming H2. There are several methods to ingest or consume H2, including inhaling hydrogen gas, drinking H2-dissolved water (hydrogen water), taking a hydrogen bath, injecting H2- dissolved saline (hydrogen saline), dropping hydrogen saline onto the eye, and increasing the production of intestinal H2 by bacteria. Since the publication of the first H2 paper in Nature Medicine in 2007, the biological effects of H2 have been confirmed by the publication of more than 38 diseases, physiological states and clinical tests in leading biological/medical journals, and several groups have started clinical examinations. Moreover, H2 shows not only effects against oxidative stress, but also various anti-inflammatory and antiallergic effects. H2 regulates various gene expressions and protein-phosphorylations, though the molecular mechanisms underlying the marked effects of very small amounts of H2 remain elusive.

Regulation of cellular redox balances is important for the homeostasis of human health. Thus, many important human diseases, such as inflammation, diabetes, glaucoma, cancers, ischemia and neurodegenerative diseases, have been investigated in the field of reactive oxygen species (ROS) and oxidative stress. To overcome the harmful effect of oxidative stress and ROS, one can directly eliminate them by medical gases such as carbon monoxide (CO), hydrogen sulphide (H2S), and molecular hydrogen (H2), or one can induce ROSresistant proteins and antioxidant enzymes to antagonize oxidative stresses. This article reviews the molecular mechanisms how these medical gasses work as antioxidants, and how ROS resistant proteins are produced in the physiological context. Targeted therapeutic modalities to scavenge or prevent ROS might be applied in the prevention and treatment of ROS-related diseases in the near future.

Glycogen synthase kinase (GSK-3) is a key enzyme in multiple cell processes. Since many pharmacological compounds that have effects on common metabolic pathways may have uses in many different diseases, we review here the possible involvement of glycogen synthase kinase 3 in diabetes, cancer and CNS diseases. Moreover, diabetes has recently been strongly linked to CNS diseases such as schizophrenia and bipolar illness. GSK-3 is both directly and indirectly inhibited by lithium, a key compound for treatment of bipolar disorder. Several antipsychotic drugs also affect the GSK-3 mediated pathways and postmortem study of brain in schizophrenia led to reports of alterations of GSK-3 activity or mRNA message. However, other reports are contradictory. Development of GSK-3 inhibitors for CNS diseases is complicated by the importance of GSK-3 in glucose metabolism and pancreas function and the possible effect of GSK-3 inhibition to be oncogenic. Further development of GSK-3 inhibitors for clinical trials should be approached with caution.

Senescent cells show a series of alterations, including a flat and enlarged morphology, increase in nonspecific acidic β- galactosidase activity, chromatin condensation, and changes in gene expression patterns. The onset and maintenance of senescence are regulated by two tumor suppressor proteins, p53 and Rb, whose expression is controlled by two distinct proteins, p19Arf and p16Ink4a, respectively, which are encoded by the cdkn2a locus. Transcription factor Jun dimerization protein 2 (JDP2) which binds directly to histones and DNA, inhibits the acetylation and methylation of core histones and of reconstituted nucleosomes that contain JDP2-recognition DNA sequences. JDP2-deficient mouse embryonic fibroblasts are known to be resistant to replicative senescence. Oxygen induces the expression of the JDP2 gene and JDP2 then inhibits the recruitment of polycomb repressive complexes (PRCs1 and 2) to the promoter of the gene encoding p16Ink4a, resulting in the inhibition of methylation of lysine 27 of histone H3. These findings suggest that chromatinremodeling factors, including the PRC complex controlled by JDP2, are important players in the senescence. The newly defined mechanisms that underlie the action of oxygen in the induction of JDP2 and cellular senescence are reviewed.

Reactive oxygen species (ROS), by-products of aerobic metabolism, cause oxidative damage to cells and tissue and not surprisingly many theories have arisen to link ROS-induced oxidative stress to aging and health. While studies clearly link ROS to a plethora of divergent diseases, their role in aging is still debatable. Genetic knock-down manipulations of antioxidants alter the levels of accrued oxidative damage, however, the resultant effect of increased oxidative stress on lifespan are equivocal. Similarly the impact of elevating antioxidant levels through transgenic manipulations yield inconsistent effects on longevity. Furthermore, comparative data from a wide range of endotherms with disparate longevity remain inconclusive. Many long-living species such as birds, bats and mole-rats exhibit high-levels of oxidative damage, evident already at young ages. Clearly, neither the amount of ROS per se nor the sensitivity in neutralizing ROS are as important as whether or not the accrued oxidative stress leads to oxidative-damage-linked age-associated diseases. In this review we examine the literature on ROS, its relation to disease and the lessons gleaned from a comparative approach based upon species with widely divergent responses. We specifically focus on the longest lived rodent, the naked mole-rat, which maintains good health and provides novel insights into the paradox of maintaining both an extended healthspan and lifespan despite high oxidative stress from a young age.

Dendrimers are polymeric compounds with highly branched structures and functionally tunable peripheral groups. Because of their low polydispersity, high degree of molecular uniformity, and precisely controlled structure, dendrimers are excellent models for demonstrating a variety of biological activities. With the attachment of metals ions and/or metals, metallodendrimers or dendrimer nanocomposites, respectively, provide diverse characters for a variety of applications. Functionalization with additional moieties, such as targeted peptides or chromophores, yields metallodendrimers that can find powerful applications and exceed the capabilities of nondendritic molecules or small molecule analogs. This review introduces the background of metallodendrimers and dendrimer nanocomposites. Biomedical applications of metallodendrimers and dendrimer nanocomposites will be discussed, including biomimetic catalysts, imaging contrast agents (especially for MRI imaging), or biomedical sensors and therapeutic agents.

Magnetic nanoparticles (MNPs) have been designed for multifaceted applications such as contrast agents in magnetic resonance imaging (MRI) diagnosis, drug/gene carriers for different kinds of therapeutic agents, tissue repair, hyperthermia, immunoassay, and cell separation/sensing. This review highlights synthesis methods, stabilizers used for surface coating on MNPs, and target ligands for ferrying payloads to an interested disease area. Some of the recent biomedical applications of MNPs in the field of drug and DNA targeting delivery are extensively reviewed.

Blood transfusion systems have greatly benefited human health and welfare. Nevertheless, some problems remain: possibility of infection, blood type mismatching, immunological response, and a short shelf life that is insufficient for stockpiling for emergency situations. Realization of artificial O2 carriers is anticipated to solve such problems. During the long development of hemoglobin (Hb)-based O2 carriers, many side effects of cell-free Hb molecules have arisen, and have implied the physiological importance of the cellular structure of red blood cells (RBCs). Therefore, Hb-vesicles (HbVs) have been developed as artificial red cells that encapsulate a concentrated Hb solution in thin lipid bilayer vesicles. This Hb encapsulation can shield various toxic effects of molecular Hbs, especially reactions with endogenous NO and CO as vasorelaxation factors. Physicochemical analyses have clarified that Hb encapsulation retards these gaseous reactions significantly. “Gas Bioengineering” is intended to create systems using bioengineering and chemical engineering techniques to facilitate the transport of or regulate the concentration of endogenous or exogenous gaseous molecules (such as O2, NO, and CO) that are sometimes vital and sometimes toxic to humans. Gas bioengineering using HbVs underscores the potential of HbVs as a transfusion alternative and promises its use for other clinical applications that remain unattainable using RBC transfusion.

There are several different ways for cancer treatment including operation, radiation therapy, chemotherapy, gene therapy, immunotherapy, ablation and hyperthermia. Techniques utilizing temperature elevation over the tumor region are usually called as thermal therapies. In this paper, we will focus on hyperthermia which is one of the promising cancer treatments utilizing the difference of thermal sensitivity between the tumor and normal tissue. In addition, microwave energy is a heating source used for localized hyperthermia. Depending on the position and size of the target tumor, several types of antennas, which radiate microwave energy to the target, can be selected. This paper describes two types of heating schemes which can be used with microwave energy, and provides brief explanations of the basic engineering involved. In addition, methods used for evaluations of antenna performance are described.

Willis, CL and Davis TP. Chronic Inflammation Pain and the Neurovascular Unit: A Central Role for Glia in Maintaining BBB Integrity. Curr Pharm Des 2008, 14: 1625-1643. Erroneously, there was an omission of Brooks, TA in the authorship for the submitted manuscript. The author list should instead read: Willis, CL, Brooks, TA and Davis TP.