NADPH oxidases as therapeutic targets in ischemic stroke

Reactive oxygen species (ROS) act physiologically as signaling molecules. In pathological conditions, such as ischemic stroke, ROS are released in excessive amounts and upon reperfusion exceed the body's antioxidant detoxifying capacity. This process leads to brain tissue damage during reoxygenation. Consequently, antioxidant strategies have long been suggested as a therapy for experimental stroke, but clinical trials have not yet been able to promote the translation of this concept into patient treatment regimens. As an evolution of this concept, recent studies have targeted the sources of ROS generation-rather than ROS themselves. In this context, NADPH oxidases have been identified as important generators of ROS in the cerebral vasculature under both physiological conditions in general and during ischemia/reoxygenation in particular. Inhibition of NADPH oxidases or genetic deletion of certain NADPH oxidase isoforms has been found to considerably reduce ischemic injury in experimental stroke. This review focuses on recent advances in the understanding of NADPH oxidase-mediated tissue injury in the cerebral vasculature, particularly at the level of the blood-brain barrier, and highlights promising inhibitory strategies that target the NADPH oxidases.     

Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases

In recent years the etiopathology of a number of debilitating diseases such as type 2 diabetes, arthritis, atherosclerosis, psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis has increasingly been linked to runaway cytokine-mediated inflammation. Cytokine-based therapeutic agents play a major role in the treatment of these diseases. However, the temporospatial changes in various cytokines are still poorly understood and attempts to date have focused on the inhibition of specific cytokines such as TNF-α. As an alternative approach, a number of preclinical studies have confirmed the therapeutic potential of targeting alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines. This “cholinergic anti-inflammatory pathway” modulates the immune system through cholinergic mechanisms that act on alpha7 receptors expressed on macrophages and immune cells. If the preclinical findings translate into human efficacy this approach could potentially provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory components.     

Endothelial epsins as regulators and potential therapeutic targets of tumor angiogenesis

VEGF-driven tumor angiogenesis has been validated as a central target in several tumor types deserving of continuous and further considerations to improve the efficacy and selectivity of the current therapeutic paradigms. Epsins, a family of endocytic clathrin adaptors, have been implicated in regulating endothelial cell VEGFR2 signaling, where its inactivation leads to nonproductive leaky neo-angiogenesis and, therefore, impedes tumor development and progression. Targeting endothelial epsins is of special significance due to its lack of affecting other angiogenic-signaling pathways or disrupting normal quiescent vessels, suggesting a selective modulation of tumor angiogenesis. This review highlights seminal findings on the critical role of endothelial epsins in tumor angiogenesis and their underlying molecular events, as well as strategies to prohibit the normal function of endogenous endothelial epsins that capitalize on these newly understood mechanisms.     

Dendritic reticulum cells in AIDS-related lymphadenopathy

Summary One of two cases of acquired immune deficiency syndrome-related persistent generalized lymphadenopathy revealed a profoundly altered pattern of dendritic reticulum cells as demonstrated by immunoreactive acid cysteine proteinase inhibitor. The alterations could be related to totally or partially destructed lymphoid secondary follicles.Acknowledgments. This work has been partially supported by the grant from the Sigrid Juselius Foundation, Finland.     

Dendritic reticulum cells in AIDS-related lymphadenopathy

One of two cases of acquired immune deficiency syndrome-related persistent generalized lymphadenopathy revealed a profoundly altered pattern of dendritic reticulum cells as demonstrated by immunoreactive acid cysteine proteinase inhibitor. The alterations could be related to totally or partially destructed lymphoid secondary follicles.     

Nitric oxide synthases: targets for therapeutic strategies in neurological diseases

Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in cooperation with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurious effects of NO derived from neuronal or inducible isoforms. New neuroprotective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400 W) isoforms or with compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The efficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases.     

G proteins as drug targets

The structure and function of heterotrimeric G protein subunits is known in considerable detail. Upon stimulation of a heptahelical receptor by the appropriate agonists, the cognate G proteins undergo a cycle of activation and deactivation; the α-subunits and the βγ-dimers interact sequentially with several reaction partners (receptor, guanine nucleotides and effectors as well as regulatory proteins) by exposing appropriate binding sites. For most of these domains, low molecular weight ligands have been identified that either activate or inhibit signal transduction. These ligands include short peptides derived from receptors, G protein subunits and effectors, mastoparan and related insect venoms, modified guanine nucleotides, suramin analogues and amphiphilic cations. Because compounds that act on G proteins may be endowed with new forms of selectivity, we propose that G protein subunits may therefore be considered as potential drug targets. Received 18 September 1998; received after revision 6 November 1998; accepted 11 November 1998     

Telomeres and telomerase as targets for cancer therapy

Telomeres are protective structures located at the ends of all eukaryotic chromosomes. Telomere shortening upon cell division restricts the proliferative capacity of most normal human cells due to the lack of telomerase, an enzyme synthesizing telomeric DNA de novo. Since most tumor cells are reliant on the activity of telomerase to maintain the stability of predominantly short individual telomeres, inhibition of this enzyme presents an attractive approach for a mechanism-based anticancer therapy. Here, we review advances and obstacles in targeting telomerase and telomeres and discuss potential applications of such approaches for the clinic. Received 9 November 2006; received after revision 8 December 2006; accepted 17 January 2007     

From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner's syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner's syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed.     

Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis

Neurodegenerative disorders are characterized by the selective vulnerability and progressive loss of discrete neuronal populations. Non-neuronal cells appear to significantly contribute to neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS), Parkinson, and Alzheimer’s disease. In ALS, there is deterioration of motor neurons in the cortex, brainstem, and spinal cord, which control voluntary muscle groups. This results in muscle wasting, paralysis, and death. Neuroinflammation, characterized by the appearance of reactive astrocytes and microglia as well as macrophage and T-lymphocyte infiltration, appears to be highly involved in the disease pathogenesis, highlighting the involvement of non-neuronal cells in neurodegeneration. There appears to be cross-talk between motor neurons, astrocytes, and immune cells, including microglia and T-lymphocytes, which are subsequently activated. Currently, effective therapies for ALS are lacking; however, the non-cell autonomous nature of ALS may indicate potential therapeutic targets. Here, we review the mechanisms of action of astrocytes, microglia, and T-lymphocytes in the nervous system in health and during the pathogenesis of ALS. We also evaluate the therapeutic potential of these cellular populations, after transplantation into ALS patients and animal models of the disease, in modulating the environment surrounding motor neurons from pro-inflammatory to neuroprotective. We also thoroughly discuss the recent advances made in the field and caveats that need to be overcome for clinical translation of cell therapies aimed at modulating non-cell autonomous events to preserve remaining motor neurons in patients.     

Polyisoprenyl glycolipids as targets of CD1-mediated T cell responses

T cells are well known to recognize peptide antigens presented by major histocompatibility (MHC) class I or class II molecules. More recently, the CD1 family of antigen-presenting molecules has been shown to present both mammalian and microbial glycolipid antigens for specific recognition by T cells. Human CD1c proteins mediate T cell recognition of polyisoprenyl glycolipids, evolutionarily conserved phosphoglycolipids, which function in glycan synthesis pathways. This family of antigenic molecules is particularly attractive for the study of the molecular features that control T cell recognition of self and foreign glycolipids because natural polyisoprenols from mammals, fungi, protozoa, mycobacteria and eubacteria differ in structure. Moreover, these naturally occurring structural differences can influence their recognition by CD1c-restricted T cells. This review of the structural diversity and evolutionary relationships of polyisoprenoid glycolipids emphasizes those features of polyisoprenyl glycolipid biosynthesis that are relevant to their functions as targets of CD1-mediated T cell responses. Received 16 March 2001; received after revision 19 April 2001; accepted 23 April 2001     

The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases

Therapy approaches based on lowering levels of pathogenic autoantibodies represent rational, effective, and safe treatment modalities of autoimmune diseases. The neonatal Fc receptor (FcRn) is a major factor regulating the serum levels of IgG antibodies. While FcRn-mediated half-life extension is beneficial for IgG antibody responses against pathogens, it also prolongs the serum half-life of IgG autoantibodies and thus promotes tissue damage in autoimmune diseases. In the present review article, we examine current evidence on the relevance of FcRn in maintaining high autoantibody levels and discuss FcRn-targeted therapeutic approaches. Further investigation of the FcRn-IgG interaction will not only provide mechanistic insights into the receptor function, but should also greatly facilitate the design of therapeutics combining optimal pharmacokinetic properties with the appropriate antibody effector functions in autoimmune diseases.