Autophagy in the physiology and pathology of the central nervous system

Neurons are highly specialized postmitotic cells that depend on dynamic cellular processes for their proper function.These include among others, neuronal growth and maturation, axonal migration, synapse formation and elimination, all requiring continuous protein synthesis and degradation. Therefore quality-control processes in neurons are directly linked to their physiology. Autophagy is a tightly regulated cellular degradation pathway by which defective or superfluouscytosolic proteins, organelles and other cellular constituents are sequestered in autophagosomes and delivered to lysosomes for degradation. Here we present emerging evidence indicating that constitutive autophagic fluxin neurons has essential roles in key neuronal processes under physiological conditions.Moreover, we discuss how perturbations of the autophagic pathway may underlie diverse pathological phenotypes in neurons associated with neurodevelopmental and neurodegenerative diseases.     

Multiple Roles of Peroxiredoxins in Inflammation

Inflammation is a pathophysiological response to infection or tissue damage during which high levels of reactive oxygen and nitrogen species are produced by phagocytes to kill microorganisms. Reactive oxygen and nitrogen species serve also in the complex regulation of inflammatory processes. Recently, it has been proposed that peroxiredoxins may play key roles in innate immunity and inflammation. Indeed, peroxiredoxins are evolutionarily conserved peroxidases able to reduce, with high rate constants, hydrogen peroxide, alkyl hydroperoxides and peroxynitrite which are generated during inflammation. In this minireview, we point out different possible roles of peroxiredoxins during inflammatory processes such as cytoprotective enzymes against oxidative stress, modulators of redox signaling, and extracellular pathogen- or damage-associated molecular patterns. A better understanding of peroxiredoxin functions in inflammation could lead to the discovery of new therapeutic targets.     

Local Dynamics During the Mixing of Saliva with a Model Colloidal Food

The events occurring during the spontaneous mixing of an okra mucilage-based model liquid food with saliva were recorded, with a focus on the local dynamics of colloidal particles contained therein. An okra mucilage containing fluorescent microsphere probes (assuming the role of model emulsion droplets), was brought into contact with reconstituted saliva on the welled slide of a confocal microscope. The movement of the probes at the saliva–mucilage interface and in the bulk mucilage has been recorded over periods of 60 min. Data have been obtained on the total mobility of individual model droplets, their diffusion coefficients, and the local viscosities, providing information on the dynamics of processes which occur during the oral processing of colloidal liquids. The role of osmotic pressure gradients on the spreading of the droplets into saliva is discussed in relation to the microrheology data.     

Successful treatment with the mTOR inhibitor everolimus in a patient with Perivascular epithelioid cell tumor

ABSTRACT: Perivascular epithelioid cell tumor (PEComa) is an extremely rare neoplasm that appears to arise most commonly at visceral (especially gastrointestinal and uterine), retroperitoneal, and abdominopelvic sites. Malignant PEComas exist but are very rare. These tumors represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. Metastatic PEComa is a rare form of sarcoma for which no effective therapy has been described previously and that has a uniformly fatal outcome. Although there is no known effective therapy, the molecular pathophysiology of aberrant mTOR signaling provides a scientific rationale to target this pathway therapeutically. The difficulty in determining optimal therapy, owing to the sparse literature available, led us to present this case. On this basis, we report a case of metastatic retroperitoneal PEComa treated with an oral mTOR inhibitor, with everolimus achieving significant clinical response.     

Hyperpolarization-activated cyclic-nucleotide gated 4 (HCN4) protein is expressed in a subset of rat dorsal root and trigeminal ganglion neurons

Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels are active at resting membrane potential and thus are likely to contribute to neuronal excitability. Four HCN channel subunits (HCN1–4) have previously been cloned. The aim of the current study was to investigate the immunoreactivity of HCN4 channel protein in rat trigeminal (TG) and dorsal root ganglion (DRG) sensory neurons. HCN4 was present in 9% of TG neurons and 4.7% of DRG neurons, it was distributed in a discrete population of small-diameter neurons in the TG but was located in cells of all sizes in the DRG. Approximately two thirds of HCN4-containing neurons in each ganglia were labelled with antisera raised against the 200-kDa neurofilament (NF200). The remaining HCN4-containing neurons were NF200-negative, were not labelled with antisera raised against calcitonin-gene related peptide (CGRP), and did not bind the isolectin B4 (IB4). HCN4-containing neurons made up more than half of the population of small-diameter primary afferent neurons that did not contain either NF200 or CGRP or bind IB4 in both TG and DRG. This population was not insignificant, comprising 5% of TG neurons and 2% of DRG neurons.     

Chromosomal and proteome analysis of a new T24‐based cell line model for aggressive bladder cancer

Cell line models aid in understanding cancer aggressiveness. The aim of this study was the establishment of a metastatic variant (T24M) of the T24 bladder cancer cell line and its initial characterization at chromosomal and proteomic levels. T24M were spontaneously developed in mice from T24 cells, following cycles of subcutaneous injections and culture in vitro. Transwell migration assays and injections in mice revealed increased migration and tumorigenic properties of T24M compared to the T24 cells. Cytogenetic analysis demonstrated that T24M retained several karyotypic characteristics of the parental cells and also acquired novel chromosomal aberrations related to aggressive bladder cancer. Proteomic analysis of the T24 and T24M cells by 2‐DE and MS led to the generation of their 2‐DE proteomic map and revealed differences in multiple proteins. These include proteases of the lysosomal and proteasome degradation pathways, mitochondrial and cytoskeletal proteins. The 2‐DE findings were confirmed by immunoblotting of cell lysates and immunohistochemistry of bladder cancer tissue sections for cathepsin D and activity assays for proteasome. Collectively, our results suggest that the T24M cells reflect many known chromosomal and proteomic aberrations encountered in aggressive bladder cancers but also provide access to novel findings with potentially clinical applications.     

Functional morphology of mouthparts and digestive system during larval development of the cleaner shrimp Lysmata amboinensis (de Man, 1888)

Mouthpart and alimentary canal development was examined in Lysmata amboinensis larvae using scanning electron microscopy and histology. The gross morphological features of external mouthparts and internal digestive tract structures of larvae at different developmental stages indicate that ingestive and digestive capabilities are well developed from early on. With increasing age of the larvae the mouthpart appendages increased in size, the hepatopancreas in tubular density and the midgut in length. The density of setae and robustness of teeth and spines of individual structures increased. The most pronounced changes from early to late stage larvae involved formation of pores on the paragnaths and labrum, transformation of the mandibular spine‐like teeth to molar cusps, development of the filter press in the proventriculus and of infoldings in the previously straight hindgut. The results suggest that early stage L. amboinensis larvae may benefit from soft, perhaps gelatinous prey, whereas later stages are better equipped to handle larger, muscular or more fibrous foods. J. Morphol. 2011. © 2011 Wiley‐Liss, Inc.