The role of human coactosin-like protein in neurodegenerative disorders

Coactosin is one of the numerous actin-binding proteins which regulate the actin cytoskeleton. Coactosin binds F-actin, and also interacts with 5-lipoxygenase, which is the first committed enzyme in leukotriene biosynthesis. Coactosin and human coactosin like protein 1 (COTL1) have the potential to play a role in the degradation or impairment of neuronal cells and their functioning. Its homology to other proteins that affect neuronal cells also contributes to this notion. The objective of this review is to explore its structural novelty, regulation and its significance in neurodegenerative diseases

Comparing the potential renal protective activity of desferrioxamine B and the novel chelator desferrioxamine B-N-(3-hydroxyadamant-1-yl) carboxamide in a cell model of myoglobinuria

Accumulating Mb (myoglobin) in the kidney following severe burns promotes oxidative damage and inflammation, which leads to acute renal failure. The potential for haem-iron to induce oxidative damage has prompted testing of iron chelators [e.g. DFOB (desferrioxamine B)] as renal protective agents. We compared the ability of DFOB and a DFOB-derivative {DFOB-AdAOH [DFOB-N-(3-hydroxyadamant-1-yl)carboxamide]} to protect renal epithelial cells from Mb insult. Loading kidney-tubule epithelial cells with dihydrorhodamine-123 before exposure to 100 μM Mb increased rhodamine-123 fluorescence relative to controls (absence of Mb), indicating increased oxidative stress. Extracellular Mb elicited a reorganization of the transferrin receptor as assessed by monitoring labelled transferrin uptake with flow cytometry and inverted fluorescence microscopy. Mb stimulated HO-1 (haem oxygenase-1), TNFα (tumour necrosis factor α), and both ICAM (intercellular adhesion molecule) and VCAM (vascular cell adhesion molecule) gene expression and inhibited epithelial monolayer permeability. Pre-treatment with DFOB or DFOB-AdAOH decreased Mb-mediated rhodamine-123 fluorescence, HO-1, ICAM and TNFα gene expression and restored monolayer permeability. MCP-1 (monocyte chemotactic protein 1) secretion increased in cells exposed to Mb-insult and this was abrogated by DFOB or DFOB-AdAOH. Cells treated with DFOB or DFOB-AdAOH alone showed no change in permeability, MCP-1 secretion or HO-1, TNFα, ICAM or VCAM gene expression. Similarly to DFOB, incubation of DFOB-AdAOH with Mb plus H2O 2 yielded nitroxide radicals as detected by EPR spectroscopy, indicating a potential antioxidant activity in addition to metal chelation; Fe(III)-loaded DFOB-AdAOH showed no nitroxide radical formation. Overall, the chelators inhibited Mb-induced oxidative stress and inflammation and improved epithelial cell function. DFOB-AdAOH showed similar activity to DFOB, indicating that this novel low-toxicity chelator may protect the kidney after severe burns

Chloride intracellular channel protein 1 and its role in neurodegenerative disorders and cancerous tumors

Chloride intracellular channel protein 1 (CLIC1) is a highly conserved intracellular anion channel protein, thought to perform significant roles in maintaining cellular homeostasis. The novelty of its properties by which it can exist in soluble globular form and as integral membrane protein have earned it much interest. While the absolute functional role of CLIC1 is still debated, it is undoubtedly established that activation of CLIC1 increases membrane chloride ion permeability. The versatility of its redox regulated structural transitions has led to its addition to the rare category of metamorphic proteins. Although the exact functions of CLIC1 in maintaining cellular homeostasis still remain to be elucidated, several studies strongly indicate the possible involvement of CLIC1 up regulation in various disease states including cancer and neurodegenerative disorders, implying its significance as a potent drug target. The objective of this review is to explore its structural novelty, regulation and roles in pathologies delineating its significance in neurodegenerative diseases

The synthetic polyphenol tert-butyl-bisphenol inhibits myoglobin-induced dysfunction in cultured kidney epithelial cells

Rhabdomyolysis caused by severe burn releases extracellular myoglobin (Mb) that accumulates in the kidney and urine (maximum [Mb] ∼ 50 μM) (termed myoglobinuria). Extracellular Mb can be a pro-oxidant. This study cultured Madin-Darby-canine-kidney-Type-II (MDCK II) cells in the presence of Mb and tested whether supplementation with a synthetic tert-butyl-polyphenol (tert-butyl-bisphenol; t-BP) protects these renal cells from dysfunction. In the absence of t-BP, cells exposed to 0100 μM Mb for 24 h showed a dose-dependent decrease in ATP and the total thiol (TSH) redox status without loss of viability. Gene expression of superoxide dismutases-1/2, haemoxygenase-1 and tumour necrosis factor increased and receptor-mediated endocytosis of transferrin and monolayer permeability decreased significantly. Supplementation with t-BP before Mb-insult maintained ATP and the TSH redox status, diminished antioxidant/pro-inflammatory gene responses, enhanced monolayer permissiveness and restored transferrin uptake. Overall, bolstering the total antioxidant capacity of the kidney may protect against oxidative stress induced by experimental myoglobinuria

Autophagy is up regulated in a neuronal model of Charcot-Marie-Tooth disease that overexpresses dynamin 2 mutant

Dominant-Intermediate Charcot-Marie-Tooth disease is one of the most common inherited disorders affecting the peripheral nervous system. Pleckstrin homology domain mutations in dynamin 2 cause dominant-intermediate Charcot Marie Tooth Syndrome. Autophagy in normal cells helps to maintain homeostasis and degrade damaged or old organelles and proteins. Here we link the pleckstrin homology domain mutants and the disease state to autophagy. Cells over-expressing the K558E mutation in the pleckstrin homology domain of dynamin 2 have shown an increase in expression of ER stress and autophagy markers. Although the exact link between autophagy and peripheral neurodegeneration has yet to be fully elucidated, these results set the foundation for further research into the interactions between dynamin 2 mutations, autophagy, and Dominant-Intermediate Charcot-Marie-Tooth

Identifying unique protein alterations caused by SPTLC1 mutations in a transfected neuronal cell model

Hereditary sensory neuropathy type I is an autosomal dominant disorder that affects the sensory neurons. Three missense mutations in serine palmitoyltransferase long chain subunit 1 cause hereditary sensory neuropathy type I. The endoplasmic reticulum, where the serine palmitoyltransferase long chain subunit 1 protein resides, and mitochondria are both altered in hereditary sensory neuropathy type I mutant cells. Employing a transfected neuronal cell line (ND15), we have identified and confirmed altered protein expression levels of ubiquinol cytochrome C, Hypoxia Up regulated Protein 1, Chloride Intracellular Channel Protein 1, Ubiqutin-40s Ribosomal Protein S27a, and Coactosin. Additionally, further 14 new proteins that exhibited altered expression within V144D, C133W and C133Y mutants were identified. These data have shown that mutations in SPTLC1 alter the expression of a set of proteins that may help to establish a causal link between the mitochondria and ER and the “dying back” process of dorsal root ganglion neurons that occurs in HSN-I

Cosupplementation with a synthetic, lipid-soluble polyphenol and vitamin C inhibits oxidative damage and improves vascular function yet does not inhibit acute renal injury in an animal model of rhabdomyolysis

We investigated whether cosupplementation with synthetic tetra-tert-butyl bisphenol (BP) and vitamin C (Vit C) ameliorated oxidative stress and acute kidney injury (AKI) in an animal model of acute rhabdomyolysis (RM). Rats were divided into groups: Sham and Control (normal chow), and BP (receiving 0.12% w/w BP in the diet; 4 weeks) with or without Vit C (100 mg/kg ascorbate in PBS ip at 72, 48, and 24 h before RM induction). All animals (except the Sham) were treated with 50% v/v glycerol/PBS (6 mL/kg injected into the hind leg) to induce RM. After 24 h, urine, plasma, kidneys, and aortae were harvested. Lipid oxidation (assessed as cholesteryl ester hydroperoxides and hydroxides and F 2-isoprostanes accumulation) increased in the kidney and plasma and this was coupled with decreased aortic levels of cyclic guanylylmonophosphate (cGMP). In renal tissues, RM stimulated glutathione peroxidase (GPx)-4, superoxide dismutase (SOD)-1/2 and nuclear factor kappabeta (NFκβ) gene expression and promoted AKI as judged by formation of tubular casts, damaged epithelia, and increased urinary levels of total protein, kidney-injurymolecule-1 (KIM-1), and clusterin. Supplementation with BP ± Vit C inhibited the two indices of lipid oxidation, down-regulated GPx-4, SOD1/2, and NF-κβ gene responses and restored aortic cGMP, yet renal dysfunction and altered kidney morphology persisted. By contrast, supplementation with Vit C alone inhibited oxidative stress and diminished cast formation and proteinuria, while other plasma and urinary markers of AKI remained elevated. These data indicate that lipid- and watersoluble antioxidants may differ in terms of their therapeutic impact on RM-induced renal dysfunctio

Phenolic antioxidants tert-butyl-bisphenol and vitamin E decrease oxidative stress and enhance vascular function in an animal model of rhabdomyolysis yet do not improve acute renal dysfunction

Rhabdomyolysis (RM) caused by severe burn releases extracellular myoglobin (Mb) that accumulates in the kidney. Extracellular Mb is a pro-oxidant. This study tested whether supplementation with tert-butyl-bisphenol (BP) or vitamin E (Vit E, as α-tocopherol) at 0.12% w/w in the diet inhibits acute renal failure (ARF) in an animal model of RM. After RM-induction in rats, creatinine clearance decreased (p < 0.01), proteinuria increased (p < 0.001) and renal-tubule damage was detected. Accompanying ARF, biomarkers of oxidative stress (lipid oxidation and hemeoxygenase-1 (HO-1) gene and protein activity) increased in the kidney (p < 0.05). Supplemented BP or Vit E decreased lipid oxidation (p < 0.05) and HO-1 gene/activity and restored aortic cyclic guanylyl monophosphate in control animals (p < 0.001), yet ARF was unaffected. Antioxidant supplementation inhibited oxidative stress, yet was unable to ameliorate ARF in this animal model indicating that oxidative stress in kidney and vascular cells may not be causally related to renal dysfunction elicited by RM