Current Molecular Medicine - Volume 11, Issue 3, 2011

Current Molecular Medicine marks its 11th anniversary with the publication of the issue 2 of volume 11. As a bimonthly journal publishing peer-reviewed articles in the field of biomedicine, CMM has been steadily growing up with the most recent impact factor reported to be 5.096. This success has been derived from the hard work and dedication of the two former Editors-in-Chief, Dr. Anil Mukherjee and Dr. Anirban Maitra, as well as the Editorial Board members. I would like to take this opportunity to thank Dr. Anil Mukherjee, Dr. Anirban Maitra and all the editorial members for their outstanding service to CMM. It is an incredible privilege to have been invited by Bentham Publishers to succeed Dr. Maitra and serve as the Editor-in-Chief for CMM. In my editorship, every effort will be made to maintain and outdo the high standards and quality that CMM has achieved. In addition, changes will be made so that exciting and important new discoveries will be published in this major biomedical journal. Starting from issue 6 of volume 11, CMM will publish research articles besides the in-depth review articles of fundamental importance in various fields of biomedical sciences. In this issue 3 under my editorship, 6 articles have been selected. Aids is a deadly disease threatening millions of life. The virus (HIV)-mediating the infection is characterized by numerous abnormalities in the immune system: massive decrease of CD4+ T cells, progressive depletion of naive CD8+ T cells, elevated numbers of apoptotic B and T cells, and systemic immune activation. These abnormalities result in the occurrence of non-functional cytotoxic T lymphocytes that fail to control HIV-replication in most individuals during the progressive phase of the disease. The costimulatory and -inhibitory molecules are also implicated in the activation, differentiation and survival of various types of cells in the immune system, and thus, HIV-infection is also characterized by an aberrant expression of these molecules on cells of the immune system. The first article by Aerts's group reviewed the functions and expression patterns of the receptor/ligand pairs of the tumor necrosis factor and the B7 super-families of costimulatory and -inhibitory molecules in HIV-infected patients. These authors also discussed the possibilities of manipulating their signaling as a therapeutic anti-HIV tool. Autophagy is one of the major catabolic processes present in eukaryotic cells. A hallmark of the autophagic pathway is the formation of double or multiple layered membranes that engulf the material to be finally degraded in the lysosomes. While enormous advances emerged in recent years in understanding the autophagic process at the molecular level, the origin of the sequestering membrane has remained elusive for more than forty years. The second article by Militello and Colombo summarized recent experimental evidence and suggested that more than one membrane source may exist. The authors also suggested that during the biogenesis of the sequestering membrane, the functions of specific organelles were necessary. Autism is a developmental disorder of the central nervous system characterized by impairments in social interaction, communication and restricted repetitive and stereotyped behavior. The mechanism underlying the disease remains unknown. The third article by Creemers's group summarized the experimental evidence showing that Neurobeachin (NBEA) may be a candidate gene for autism. By analyzing the functions of NBEA and its regulation on other biological processes, Creemers's group suggested that new insights towards the functions of NBEA may help in identifying novel pathways affected in autistic patients. In particular, the impaired functionality of large dense-core vesicles (LDCVs), which contain neurotrophins, neuropeptides and monoamines, might contribute to the pathogenesis of autism in at least a subgroup of patients. Hypoxia Inducible Factor-1 (HIF-1) is considered the major coordinator of the cellular adaptive response to hypoxia. The fourth article by Harmon's group summarized the role of HIF-1 in regulating the process of endothelial cell survival, migration and proliferation, vascular smooth muscle cell migration and proliferation and mobilization of circulating angiogenic cells to the periphery. They further discussed the effect of HIF-1 on the expression and activity of extracellular cell matrix modifying enzymes including MMPs and prolidase in the context of tumor angiogenesis and metastasis, and suggested that HIF-1 also may play an important role in wound healing. Classical Hodgkin lymphoma (cHL) is now recognized as a B-cell-derived lymphoma characterized by few malignant pathognomonic Hodgkin and Reed-Sternberg (HRS) cells and an abundant infiltrate of reactive bystander cells. The fifth article by Schwarzer and Jundt summarized the properties of the HRS cells and then discussed the roles of the Notch and NF-κB signaling pathways (see cover figure) for cHL pathogenesis, their potential cross-talk and implications for future therapeutic applications. Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease. The cause remains unknown. The last article by McCombe and Henderson explored the role of immune and inflammatory mechanisms in ALS after a discussion of both genetic abnormalities and environment factors. In summary, these articles touch fundamental aspects of different human diseases, which will provide valuable formation to the colleagues in the corresponding fields.

HIV infection is characterized by a number of abnormalities in several components of the immune system. For example, during HIV infection, a massive decrease of CD4+ T cells is observed, as well as a progressive depletion of naive CD8+ T cells. Furthermore, elevated numbers of apoptotic B and T cells are present in HIV-infected patients, and a systemic immune activation results in T-cell exhaustion. Finally, HIV infection is characterized by the presence of functionally impaired dendritic cells, with decreased expression of maturation markers, decreased secretion of cytokines and defects in antigen processing and presentation. All these characteristics result in the occurrence of non-functional cytotoxic T lymphocytes, that fail to control HIVreplication in most individuals during progressive disease. Costimulatory and co-inhibitory molecules are involved in the activation, differentiation and survival of several cell-types of the immune system. Each costimulatory receptor (generally expressed on effector cells) can conjugate with one or more specific ligands (expressed on antigen-presenting cells), which leads to an activation of intracellular signaling pathways inside the cells on which they are expressed. HIV infection is characterized by an aberrant expression of these molecules on cells of the immune system. Many of the immune deficiencies mentioned in the previous paragraph can be explained by abnormal expression of costimulatory molecules, and could consequently be overcome by interfering with their interactions. In this review, we give an overview of the functions and expression patterns of the receptor/ligand pairs of the tumor necrosis factor and the B7 super-families of costimulatory and co-inhibitory molecules in HIV-infected patients. We will also discuss possibilities for manipulating their signaling as a therapeutic anti-HIV tool.

Autophagy is one of the major catabolic processes present in eukaryotic cells, conserved through evolution, by which damaged or superfluous organelles are degraded in response to different stimuli. A hallmark of the autophagic pathway is the formation of double or multiple layered membranes that engulf the material to be finally degraded in the lysosomes. Despite enormous advances in the last few years to understand the autophagic process at the molecular level, the origin of the sequestering membrane has remained elusive for more than forty years and it is still a matter of debate. In this review we have summarized recent experimental evidence indicating that more than one membrane source may exist. Even though de novo formation or assembly of the isolation membrane has been proposed, recent data points to the participation of specific organelles in the biogenesis of the sequestering membrane.

Autism is a developmental disorder of the central nervous system characterized by impairments in social interaction, communication and restricted repetitive and stereotyped behavior. It is generally assumed that in most cases autism has a polygenic cause, but the pathogenesis is still unknown. Neurobeachin (NBEA) has recently been identified as a candidate gene for autism in a patient with a de novo chromosomal translocation and three patients with a monoallelic deletion. This multidomain scaffolding protein has been suggested to be involved in neuronal post-Golgi membrane traffic. Knockout of Nbea in two independent mouse models has demonstrated a role in neurotransmitter release and synaptic functioning. Knockdown in a cell line has shown a role as negative regulator of secretion of large dense-core vesicles (LDCVs) and haploinsufficiency in blood platelets results in dense granules with an aberrant morphology. A potential role in vesicle transport is further supported by a study of SEL-2, the C. elegans homologue of NBEA. This protein was identified as a negative regulator of LIN-12/Notch activity, probably due to defects in endosomal trafficking. Members of the Notch pathway have also been shown to be modifiers of the NBEA homologue in Drosophila, rugose. These new insights in the function of NBEA may help identifying novel pathways affected in autistic patients. In particular, it suggests that impaired functionality of LDCVs, which contain neurotrophins, neuropeptides and monoamines, might contribute to the pathogenesis of autism in at least a subgroup of patients.

Hypoxia Inducible Factor-1 (HIF-1) is considered the major coordinator of the cellular adaptive response to hypoxia. Over recent years, its activity in the context of wound healing has been the object of increasing investigation. On the molecular level, HIF-1 transcriptional target products have been shown to regulate the process of endothelial cell survival, migration and proliferation (VEGF, ANGPT-1, ANGPT-2, ANGPT-4, FGF-2, PlGF, PDGF-B, RGC-32), vascular smooth muscle cell migration and proliferation (FGF-2, EGF, PDGF, thrombospondin) and mobilization of Circulating Angiogenic Cells to the periphery (SFD- 1/CXCR4). Studies on the effect of HIF-1 on the expression and activity of extracellular cell matrix modifying enzymes, such as MMPs and prolidase, have been conducted in the context of tumor angiogenesis and metastasis, and have resulted in controversial findings. A growing body of evidence suggests that HIF-1 also affects reepithelialization of the wound bed, through increasing keratinocyte migration, but decreasing their proliferation. Diminished HIF-1 levels and activity have been documented in conditions of impaired wound healing, such as wound healing in aged and in diabetic mice. The increasing number of studies on the role of HIF-1 in wound healing, apart from answering certain questions, has also raised an equal number, if not more. Clarifying the topics that still remain unclear could introduce a new era of HIF-1 targeted management of a wide range of problematic wounds.

Classical Hodgkin lymphoma (cHL) is now recognized as a B-cell-derived lymphoma which is characterized by only about 1% malignant pathognomonic Hodgkin and Reed-Sternberg (HRS) cells and an abundant infiltrate of reactive bystander cells. HRS cells are unique with respect to their lost B-cell-specific gene expression pattern and recurrent genetic lesions. Aberrant activity of Notch signaling, a highly conserved developmental pathway, acts as a negative regulator of the B cell program in HRS cells and thereby contributes to their reprogramming. Another striking feature and the major pathogenetic mechanism in HRS cells is constitutive NF-κB activation. A number of aberrations that contribute to canonical NF-κB activity in HRS cells have been described such as genetic lesions, deregulated receptor signaling and Epstein-Barr virus (EBV) infection. The importance of Notch and NF-κB signaling for cHL pathogenesis, their potential cross-talk and implications for future therapeutic applications are being discussed.

Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease. The cause is unknown, but genetic abnormalities have been identified in subjects with familial ALS and also in subjects with sporadic ALS. Environmental factors such as occupational exposure have been shown to be risk factors for the development of ALS. Patients differ in their clinical features and differ in the clinical course of disease. Immune abnormalities have been found in the central nervous system by pathological studies and also in the blood and CSF of subjects with ALS. Inflammation and immune abnormalities are also found in animals with a model of ALS due to mutations in the SOD1 gene. Previously it has been considered that immune abnormalities might contribute to the pathogenesis of disease. However more recently it has become apparent that an immune response can occur as a response to damage to the nervous system and this can be protective.