Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.

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Sirtuins in mammals: insights into their biological function

Claudins are tight junction membrane proteins that are expressed in epithelia and endothelia and form paracellular barriers and pores that determine tight junction permeability. This review summarizes our current knowledge of this large protein family and discusses recent advances in our understanding of their structure and physiological functions.

Claudins and the Modulation of Tight Junction Permeability

The myelination of axons by glial cells was the last major step in the evolution of cells in the vertebrate nervous system, and white-matter tracts are key to the architecture of the mammalian brain. Cell biology and mouse genetics have provided insight into axon–glia signalling and the molecular architecture of the myelin sheath. Glial cells that myelinate axons were found to have a dual role by also supporting the long-term integrity of those axons. This function may be independent of myelin itself. Myelin abnormalities cause a number of neurological diseases, and may also contribute to complex neuropsychiatric disorders.

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Myelination and support of axonal integrity by glia

Histone deacetylases (HDACs)--enzymes that affect the acetylation status of histones and other important cellular proteins--have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Pharmacological manipulations using small-molecule HDAC inhibitors--which may restore transcriptional balance to neurons, modulate cytoskeletal function, affect immune responses and enhance protein degradation pathways--have been beneficial in various experimental models of brain diseases. Although mounting data predict a therapeutic benefit for HDAC-based therapy, drug discovery and development of clinical candidates face significant challenges. Here, we summarize the current state of development of HDAC therapeutics and their application for the treatment of human brain disorders such as Rubinstein-Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntington's disease and multiple sclerosis.

Therapeutic application of histone deacetylase inhibitors for central nervous system disorders.

Myelination of axons in the nervous system of vertebrates enables fast, saltatory impulse propagation, one of the best-understood concepts in neurophysiology However, it took a long while to recognize the mechanistic complexity both of myelination by oligodendrocytes and Schwann cells and of their cellular interactions In this review, we highlight recent advances in our understanding of myelin biogenesis, its lifelong plasticity, and the reciprocal interactions of myelinating glia with the axons they ensheath In the central nervous system, myelination is also stimulated by axonal activity and astrocytes, whereas myelin clearance involves microglia/macrophages Once myelinated, the long-term integrity of axons depends on glial supply of metabolites and neurotrophic factors The relevance of this axoglial symbiosis is illustrated in normal brain aging and human myelin diseases, which can be studied in corresponding mouse models Thus, myelinating cells serve a key role in preserving the connectivity and 

Myelination of the nervous system: mechanisms and functions

Liposomes as carriers for dermal delivery of tretinoin: in vitro evaluation of drug permeation and vesicle-skin interaction.

Examination of the cytoskeleton has demonstrated the pivotal role of regulatory proteins governing cytoskeletal dynamics. Most work has focused on cell cycle and cell migration regarding cancer. However, these studies have yielded tremendous insight for development, particularly in the nervous system where all major cell types remodel their shape, generate unsurpassed quantities of membranes and extend cellular processes to communicate, and regulate the activities of other cells. Herein, we analyze two microtubule regulatory alpha-tubulin deacetylases, histone deacetylase-6 (HDAC6) and SirT2. HDAC6 is expressed by most neurons but is abundant in cerebellar Purkinje cells. In contrast, SirT2 is targeted to myelin sheaths. Expression of these proteins by post-mitotic cells indicates novel functions, such as process outgrowth and membrane remodeling. In oligodendrocytes, targeting of SirT2 to paranodes coincides with the presence of the microtubule-destabilizing protein stathmin-1 during early myelinogenesis and suggests the existence of a microtubule regulatory network that modulates cytoskeletal dynamics.

Microtubule Deacetylases, SirT2 and HDAC6, in the Nervous System

Tight junctions (TJs) are essential features of endothelial barrier membranes and of fluid-secreting epithelial cells, such as in the salivary glands. Novel integral membrane proteins have been identified as components of TJs, namely claudins and occludin. The aim of the present study was to determine the distribution of occludin and claudins in the large salivary glands of the rat. The parotid, submandibular and sublingual salivary glands were harvested from adult Sprague–Dawley rats and cryostat sections were stained using immunoperoxidase and immunofluorescence methods. Claudin-1 was expressed in endothelial cells of microvessels and in short selected segments of the duct system. Claudin-3 was expressed principally in the acinar cells and intercalated ducts, while claudin-4 was principally expressed by the striated and interlobular ducts. Claudin-5 was specific to endothelial cells of microvessels. Occludin was ubiquitously detected in the duct system. Double labelling and confocal microscopy showed some co-localization of claudin-3 with claudin-4, and minimal co-localization of occludin with claudin-4, in the striated ducts. Claudin 2 was not detected in any of the salivary glands. The results indicate specificity of the chemical composition of tight junctions in the rat salivary glands, and may reflect different physiological roles for TJs in the glandular and duct epithelial cells, and in endothelial cells of salivary gland microvessels.

Tissue‐specific expression of the tight junction proteins claudins and occludin in the rat salivary glands

Dynamic regulation of the expression of surface AMPA receptors (AMPARs) is a key mechanism to modulate synaptic strength and efficacy in the CNS and also to regulate auditory sensitivity. Here we a...

Regulated Expression of Surface AMPA Receptors Reduces Excitotoxicity in Auditory Neurons

Background: Direct delivery of drugs and other agents into the inner ear will be important for many emerging therapies, including the treatment of degenerative disorders and guiding

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Marcello Peppi

Papers

Liposomes as carriers for dermal delivery of tretinoin: in vitro evaluation of drug permeation and vesicle-skin interaction.

Microtubule Deacetylases, SirT2 and HDAC6, in the Nervous System

Tissue‐specific expression of the tight junction proteins claudins and occludin in the rat salivary glands

Regulated Expression of Surface AMPA Receptors Reduces Excitotoxicity in Auditory Neurons

Development of a Microfluidics-Based Intracochlear Drug Delivery Device