Arsenic upregulates MMP-9 and inhibits wound repair in human airway epithelial cells.: "

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Arsenic upregulates MMP-9 and inhibits wound repair in human airway epithelial cells.

Am J Physiol Lung Cell Mol Physiol. 2008 Aug;295(2):L293-302

Authors: Olsen CE, Liguori AE, Zong Y, Lantz RC, Burgess JL, Boitano S

As part of the innate immune defense, the polarized conducting lung epithelium acts as a barrier to keep particulates carried in respiration from underlying tissue. Arsenic is a metalloid toxicant that can affect the lung via inhalation or ingestion. We have recently shown that chronic exposure of mice or humans to arsenic (10-50 ppb) in drinking water alters bronchiolar lavage or sputum proteins consistent with reduced epithelial cell migration and wound repair in the airway. In this report, we used an in vitro model to examine effects of acute exposure of arsenic (15-290 ppb) on conducting airway lung epithelium. We found that arsenic at concentrations as low as 30 ppb inhibits reformation of the epithelial monolayer following scrape wounds of monolayer cultures. In an effort to understand functional contributions to epithelial wound repair altered by arsenic, we showed that acute arsenic exposure increases activity and expression of matrix metalloproteinase (MMP)-9, an important protease in lung function. Furthermore, inhibition of MMP-9 in arsenic-treated cells improved wound repair. We propose that arsenic in the airway can alter the airway epithelial barrier by restricting proper wound repair in part through the upregulation of MMP-9 by lung epithelial cells.

PMID: 18539681 [PubMed - indexed for MEDLINE]

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The membrane repair response masks membrane disturbances caused by cell-penetrating peptide uptake.

FASEB J. 2008 Sep 11;

Authors: Palm-Apergi C, Lorents A, Padari K, Pooga M, Hällbrink M

Although cell-penetrating peptides are able to deliver cargo into cells, their uptake mechanism is still not fully understood and needs to be elucidated to improve their delivery efficiency. Herein, we present evidence of a new mechanism involved in uptake, the membrane repair response. Recent studies have suggested that there might be a direct penetration of peptides in parallel with different forms of endocytosis. The direct penetration of hydrophilic peptides through the hydrophobic plasma membrane, however, is highly controversial. Three proteins involved in target cell apoptosis-perforin, granulysin, and granzymes-share many features common in uptake of cell-penetrating peptides (e.g., they bind proteoglycans). During perforin uptake, the protein activates the membrane repair response, a resealing mechanism triggered in cells with injured plasma membrane, because of extracellular calcium influx. On activation of the membrane repair response, internal vesicles are mobilized to the site of the disrupted plasma membrane, resealing it within seconds. In this study, we have used flow cytometry, fluorescence, and electron microscopy, together with high-performance liquid chromatography and mass spectrometry, to present evidence that the membrane repair response is able to mask damages caused during cell-penetrating peptide uptake, thus preventing leakage of endogenous molecules out of the cell.-Palm-Apergi, C., Lorents, A., Padari, K., Pooga, M., and Hällbrink, M. The membrane repair response masks membrane disturbances caused by cell-penetrating peptide uptake.

PMID: 18787109 [PubMed - as supplied by publisher]

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Behavioral recovery from traumatic brain injury after membrane reconstruction using polyethylene glycol.

J Biol Eng. 2008 Jun 27;2(1):9

Authors: Koob AO, Colby JM, Borgens RB

ABSTRACT: Polyethylene glycol (PEG; 2000 MW, 30% by volume) has been shown to mechanically repair damaged cellular membranes and reduce secondary axotomy after traumatic brain and spinal cord injury (TBI and SCI respectively). This repair is achieved following spontaneous reassembly of cell membranes made possible by the action of targeted hydrophilic polymers which first seal the compromised portion of the plasmalemma, and secondarily, allow the lipidic core of the compromised membranes to resolve into each other. Here we compared PEG -treated to untreated rats using a computer-managed open-field behavioral test subsequent to a standardized brain injury. Animals were evaluated after a 2-, 4-, and 6-hour delay in treatment after TBI. Treated animals received a single subcutaneous injection of PEG. When treated within 2 hours of the injury, injured PEG-treated rats showed statistically significant improvement in their exploratory behavior recorded in the activity box when compared to untreated but brain-injured controls. A delay of 4 hours reduced this level of achievement, but a statistically significant improvement due to PEG injection was still clearly evident in most outcome measures compared at the various evaluation times. A further delay of 2 more hours, however, eradicated the beneficial effects of PEG injection as revealed using this behavioral assessment. Thus, there appears to be a critical window of time in which PEG administration after TBI can provide neuroprotection resulting in an enhanced functional recovery. As is often seen in clinically applied acute treatments for trauma, the earlier the intervention can be applied, the better the outcome.

PMID: 18588669 [PubMed - as supplied by publisher]

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Caveolin-3 deficiency decreases the gene expression level of osteopontin in mdx mouse skeletal muscle.

Acta Myol. 2006 Oct;25(2):53-61

Authors: Hagiwara Y, Fujita M, Imamura M, Noguchi S, Sasaoka T

Caveolin-3 is a muscle-specific membrane protein that serves as a scaffold of various molecules. As previously reported, caveolin-3 deficiency causes muscle degeneration in mice. In the present study, gene expression profiles, analyzed in the skeletal muscles of caveolin-3 deficient mice using the DNA microarray technique, showed that the gene of osteopontin, a versatile regulator of inflammation and tissue repair, was significantly down-regulated. This is in contrast to mdx mice showing a markedly up-regulated osteopontin gene in their skeletal muscles. Recently, osteopontin has been reported to be important in the pathogenesis of muscular dystrophy. We examined whether up-regulated osteopontin gene expression in mdx muscles is altered by the deficiency of caveolin-3. To this end, we developed caveolin-3 and dystrophin double-deficient mice and used them for the analysis. Levels of osteopontin mRNA and protein in the double-deficient mice clearly decreased compared with those in mdx mice.

PMID: 18593005 [PubMed - indexed for MEDLINE]

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Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia.

Neuroscience. 2008 Jun 19;

Authors: Candelario-Jalil E, Yang Y, Rosenberg GA

Regulation of the extracellular matrix by proteases and protease inhibitors is a fundamental biological process for normal growth, development and repair in the CNS. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) are the major extracellular-degrading enzymes. Two other enzyme families, a disintegrin and metalloproteinase (ADAM), and the serine proteases, plasminogen/plasminogen activator (P/PA) system, are also involved in extracellular matrix degradation. Normally, the highly integrated action of these enzyme families remodels all of the components of the matrix and performs essential functions at the cell surface involved in signaling, cell survival, and cell death. During the inflammatory response induced in infection, autoimmune reactions and hypoxia/ischemia, abnormal expression and activation of these proteases lead to breakdown of the extracellular matrix, resulting in the opening of the blood-brain barrier (BBB), preventing normal cell signaling, and eventually leading to cell death. There are several key MMPs and ADAMs that have been implicated in neuroinflammation: gelatinases A and B (MMP-2 and -9), stromelysin-1 (MMP-3), membrane-type MMP (MT1-MMP or MMP-14), and tumor necrosis factor-alpha converting enzyme (TACE). In addition, TIMP-3, which is bound to the cell surface, promotes cell death and impedes angiogenesis. Inhibitors of metalloproteinases are available, but balancing the beneficial and detrimental effects of these agents remains a challenge.

PMID: 18621108 [PubMed - as supplied by publisher]

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Highly efficient, functional engraftment of skeletal muscle stem cells in dystrophic muscles.

Cell. 2008 Jul 11;134(1):37-47

Authors: Cerletti M, Jurga S, Witczak CA, Hirshman MF, Shadrach JL, Goodyear LJ, Wagers AJ

Satellite cells reside beneath the basal lamina of skeletal muscle fibers and include cells that act as precursors for muscle growth and repair. Although they share a common anatomical localization and typically are considered a homogeneous population, satellite cells actually exhibit substantial heterogeneity. We used cell-surface marker expression to purify from the satellite cell pool a distinct population of skeletal muscle precursors (SMPs) that function as muscle stem cells. When engrafted into muscle of dystrophin-deficient mdx mice, purified SMPs contributed to up to 94% of myofibers, restoring dystrophin expression and significantly improving muscle histology and contractile function. Transplanted SMPs also entered the satellite cell compartment, renewing the endogenous stem cell pool and participating in subsequent rounds of injury repair. Together, these studies indicate the presence in adult skeletal muscle of prospectively isolatable muscle-forming stem cells and directly demonstrate the efficacy of myogenic stem cell transplant for treating muscle degenerative disease.

PMID: 18614009 [PubMed - indexed for MEDLINE]

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Treatment of burn injury by cellular repair.

J Craniofac Surg. 2008 Jul;19(4):903-6

Authors: Dalal ND, Lee RC

Burn injury leads to a direct damaging effect on cells, disrupting the assembly of the cell and denaturing proteins. Although modern medicine has significantly improved the survival of burn victims, a method to treat injury at the cellular level is presented. In particular, the cell membrane is most vulnerable to heat injury. Copolymer surfactants have been shown to repair the cell membrane, and agents such as poloxamer 188 have demonstrated this effect in numerous studies. Furthermore, copolymer surfactants have been shown to act as molecular chaperones, allowing denatured proteins to regain their native confirmation. Pharmaceutical agents may be developed to repair the cell membrane and refold proteins, mimicking endogenous repair mechanisms and salvaging cells that would otherwise be lost.

PMID: 18650709 [PubMed - in process]

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