Chronic spinal cord injury (SCI) is difficult to cure, even by several approaches effective at the acute or subacute phase. We focused on skeletal muscle atrophy as a detrimental factor in chronic SCI and explored drugs that protect against muscle atrophy and activate secretion of axonal growth factors from skeletal muscle. We found that acteoside induced the secretion of axonal growth factors from skeletal muscle cells and proliferation of these cells. Intramuscular injection of acteoside in mice with chronic SCI recovered skeletal muscle weight reduction and motor function impairment. We also identified pyruvate kinase isoform M2 (PKM2) as a secreted factor from skeletal muscle cells, stimulated by acteoside. Extracellular PKM2 enhanced proliferation of skeletal muscle cells and axonal growth in cultured neurons. Further, we showed that PKM2 might cross the blood–brain barrier. These results indicate that effects of acteoside on chronic SCI might be mediated by PKM2 secretion from skeletal muscles. This study proposes that the candidate drug acteoside and a new myokine, PKM2, could be used for the treatment of chronic SCI.
In contrast to scales collected from the scalps of nine healthy individuals where a few parakeratotic cells are observable, a large number of parakeratotic cells associated with some infiltrated polymorphonuclear leukocytes (PMNLs) were found in the scales obtained from 11 individuals complaining of dandruff. Therefore, we determined the neutrophil chemotactic properties of the water-soluble extracts of dandruff scales and normal control scalp scales. Aqeous extracts fractionated by Sephadex G-75 showed a potent chemotactic activity only in the fractions of the dandruff patients that eluted with cytochrome C marker (cyt C; molecular weight, 12 kDa). It was comparatively stable to heat but was greatly inhibited by the addition of anti-C5 antiserum. Radioimmunoassay demonstrated that, although small amounts of C5a and C4a anaphylatoxins were demonstratable even in the extracts of normal scalp, they were found in significantly increased amounts in the extracts of dandruff. Moreover, there was a significantly positive correlation between C5a and C4a concentrations in these extracts. These results suggest that classical complement pathway activation with resultant production of C5a anaphylatoxin is involved in the migration of PMNLs into the lesional skin of dandruff.
In our previous study, we found that pyruvate kinase isoform M2 (PKM2) was secreted from the skeletal muscle and extended axons in the cultured neuron. Indirect evidence suggested that secreted PKM2 might relate to the recovery of motor function in spinal cord injured (SCI) mice. However, in vivo direct evidence has not been obtained, showing that extracellular PKM2 improved axonal density and motor function in SCI mice. In addition, the signal pathway of extracellular PKM2 underlying the increase in axons remained unknown. Therefore, this study aimed to identify a target molecule of extracellular PKM2 in neurons and investigate the critical involvement of extracellular PKM2 in functional recovery in the chronic phase of SCI. Recombinant PKM2 infusion to the lateral ventricle recovered motor function in the chronic phase of SCI mice. The improvement of motor function was associated with axonal increase, at least of raphespinal tracts connecting to the motor neurons directly or indirectly. Target molecules of extracellular PKM2 in neurons were identified as valosin-containing protein (VCP) by the drug affinity responsive target stability method. ATPase activation of VCP mediated the PKM2-induced axonal increase and recovery of motor function in chronic SCI related to the increase in axonal density. It is a novel finding that axonal increase and motor recovery are mediated by extracellular PKM2-VCP-driven ATPase activity.
One-year-old B6C3/f mice, injected with beta-crystallins emulsified with CFA, developed lens epithelial cell damage. Both serum transfer and mAb transfer studies clearly established that the autoimmune insult is induced by humoral immunity. Older mice were more susceptible to autoimmune insult than younger animals. Lens epithelial cell damage invariably proceeded to cortical and posterior subcapsular cataract formation. This mouse model of experimental autoimmune cataract formation will facilitate the exploration of the relation between immune phenomena and human age-related cataract.
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