Volume 5, Issue 4

Inflammation mediated by the crosstalk between leukocytes and resident tissue cells is crucial for the maintenance of homeostasis. Because chemokine ligands and receptors, which recruit a variety of leukocytes, are widely distributed among tissues, it is important to understand the mechanisms regulating inflammatory disease. Chemokines such as CC-chemokine ligand 2 (CCL2) amplify and maintain inflammation through chemokine-cytokine networks after the recruitment of circulating leukocytes. Chemokine-dependent nonresolving inflammation occurs in the peripheral and central nervous systems, and underlies several intractable diseases, including cancer and neuropathic pain. The chronic upregulation of chemokines is often mediated by epigenetic mechanisms consisting of DNA methylation, histone modification, and nucleosome positioning. In particular, histone acetylation and methylation have been shown to play important roles in the upregulation of chemokine expression. In addition to CCL2, several other chemokines strongly contribute to neuropathic pain through epigenetic induction. Consequently, targeting epigenetic changes may have therapeutic potential for nonresolving inflammatory diseases such as neuropathic pain. Further research into the epigenetics of inflammatory diseases should promote the development of novel and effective treatment strategies for intractable inflammatory diseases.

Non-canonical microRNAs are a recently-discovered subset of microRNAs. They structurally and functionally resemble canonical miRNAs, but were found to follow distinct maturation pathways, typically bypassing one or more steps of the classic canonical biogenesis pathway. Non-canonical miRNAs were found to have diverse origins, including introns, snoRNAs, endogenous shRNAs and tRNAs. Our knowledge about their functions remains relatively primitive; however, many interesting discoveries have taken place in the past few years. They have been found to take part in several cellular processes, such as immune response and stem cell proliferation. Adversely, their deregulation has pathologic effects on several different tissues, which strongly suggests an integral role for non-canonical miRNAs in disease pathogenesis. In this review, we discuss the recently-discovered functional characteristics of non-canonical miRNAs and illustrate their principal maturation pathways as well as debating their potential role in multiple cellular processes.

Oligodendrocytes and myelin play essential roles in the vertebrate central nervous system. Demyelination disrupts saltatory nerve conduction, leading to axonal degeneration and neurological disabilities. Remyelination is a regenerative process that replaces lost myelin. However, remyelination is disrupted in demyelinating diseases such as multiple sclerosis, at least partially, due to the failure of oligodendrocyte precursor cells to differentiate into myelinating oligodendrocytes. Understanding the molecular and cellular mechanisms that impact the differentiation of oligodendrocytes and myelination may help in the development of novel therapeutic strategies for demyelinating diseases. In this review, we focus on the molecular mechanisms controlling the differentiation of oligodendrocytes during remyelination, and we discuss the function of astrocytes and microglia in animal models of demyelinating diseases.

This review article describes the occurrence, general properties, and substrate specificity of the flavoenzymes belonging to the glucose-methanol-choline oxidoreductase superfamily and the l -α-hydroxyacid dehydrogenase family. Most of these enzymes catalyze the oxidations of hydroxyl groups, yielding carbonyl moieties. Over the years, carbanion, hydride transfer, and radical mechanisms have been discussed for these enzymes, and the main experimental evidences supporting these mechanisms are presented here. Regardless of the chemical nature of the organic substrate (i.e., activated and non-activated alcohols), a hydride transfer mechanism appears to be the most plausible for the flavoenzymes acting on CH-OH groups. The reaction of most of these enzymes likely starts with proton abstraction from the substrate hydroxyl group by a conserved active site histidine. Among the different approaches carried out to determine the chemical mechanisms with physiological substrates, primary substrate and solvent deuterium kinetic isotope effect studies have provided the most unambiguous evidences. It is expected that the numerous studies reported for these enzymes over the years will be instrumental in devising efficient industrial biocatalysts and drugs.

Podocytes are postmitotic renal glomerular cells with multiple ramifications that extend from the cell body. Processes departing from a podocyte interdigitate with corresponding projections from neighboring cells and form an intricate web that enwraps the glomerular capillary completely. Podocyte processes are interconnected by the slit diaphragm, an adhesion junction mostly formed by Ig-like molecules, cadherins/protocadherins, ephrin/eph, and neurexin molecules organized in an assembly that resembles synaptic junctions. Podocyte failure is primarily or secondarily implicated in all forms of proteinuric glomerular diseases, as confirmed by the morphological changes of their elaborate cell architecture detectable by electron microscopy. Importantly, mutations of podocyte proteins are responsible for the most severe forms of congenital nephrotic syndrome. In the last 15 years, progressive technological advances have aided the study of podocyte biology and pathology, confirming the relevance of podocyte molecules and signaling pathways for the function of the glomerular filter. This review will examine the most important and newest discoveries in the field, which is rapidly evolving, hopefully leading to a detailed knowledge of this fascinating cell and to the development of specific therapeutic options for proteinuric diseases.

Meiosis is a unique type of cell division that is performed only by germ cells to form haploid gametes. The switch from mitosis to meiosis exhibits a distinct sex-specific difference in timing, with female germ cells entering meiosis during fetal development and male germ cells at puberty when spermatogenesis is initiated. During early fetal development, bipotential primordial germ cells migrate to the forming gonad where they remain sexually indifferent until the sex-specific differentiation of germ cells is initiated by cues from the somatic cells. This irreversible step in gonadal sex differentiation involves the initiation of meiosis in fetal ovaries and prevention of meiosis in the germ cells of fetal testes. During the last decade, major advances in the understanding of meiosis regulation have been accomplished, with the discovery of retinoic acid as an inducer of meiosis being the most prominent finding. Knowledge about the molecular mechanisms regulating meiosis signaling has mainly been established by studies in rodents, while this has not yet been extensively investigated in humans. In this review, the current knowledge about the regulation of meiosis signaling is summarized and placed in the context of fetal gonad development and germ cell differentiation, with emphasis on results obtained in humans. Furthermore, the consequences of dysregulated meiosis signaling in humans are briefly discussed in the context of selected pathologies, including testicular germ cell cancer and some forms of male infertility.

Because of the variability of relevant developmental resources across different environments, and because only a portion of the genome is expressed in any individual organism as a result of its specific developmental context and experience, what is actually realized during the course of individual development represents only one of many possibilities. One conclusion to be drawn from this insight is that the origin of phenotypic traits and their variation can be traced to the process of development. In this conceptual overview, I briefly explore how recent efforts to integrate genetic, epigenetic, and environmental levels of analysis through a developmental lens is advancing our understanding of the generation of the stability and variability of phenotypic outcomes observed within and across generations. A growing body of evidence indicates that phenotypes are the outcomes of the whole developmental system, comprised of the organism, with its particular genetic and cellular make-up in its specific physical, biological, and social environments. I conclude that the emergent products of development are epigenetic, not just genetic, and evolutionary explanation cannot be complete without a developmental mode of analysis.