Added forearm weights for gait pattern normalization in patients with Parkinson's disease.

Patients with Parkinson's Disease presented gait impairment. Applying additional weights to enhancing sensory input may improve gait impairment. We assumed that gait impairment could be improved when patients walked with additional forearm weights, and the gait improvement was associated with clinical characteristic of Parkinson's Disease. Thirty patients with Parkinson's Disease and 30 age-sex matched controls were recruited. Spatiotemporal and joint kinematics parameters were evaluated by a three-dimensional motion capture system in normal walking and walking with sandbags, respectively. The comparisons of spatiotemporal parameters were analyzed using t-test or nonparametric tests. The comparison of joint kinematic data was analyzed using statistical parametric mapping. The correlation between motor symptom and gait parameters changes was analyzed using Pearson's correlation analysis. During normal walking, patients showed deteriorated gait compared with controls. After applying weights to forearms patients increased cadence (p = 0.004), speed (p < 0.001) and step length (p = 0.048), and decreased stride time (p = 0.003). The hip angles significantly increased during 5%-23% and 87%-100% of gait cycle, while knee angles during 9%-25% and 88%-98% of the gait cycle, and ankle angles in 92%-100% of gait cycle. The gait parameters of patients with forearm-loading showed no significant difference compared with healthy subjects walking normally. The change of gait parameters correlated positively with the axial and tremor severity while correlated negatively with the rigidity sub-score. Patients with tremor dominant subtype also showed greater improvement of speed and step time compared with patients with postural instability/gait difficulty subtype. Applying added weights bilaterally to the forearms of patients can normalize gait patterns. Notably, patients with higher scores on axial and tremor and lower rigidity scores gained more benefits.

sDR5-Fc inhibits macrophage M1 polarization by blocking the glycolysis.

BACKGROUND: M1 polarization of macrophages is an important pathological process in myocardial ischemia reperfusion injury, which is the major obstacle for the treatment of acute myocardial infarction. Currently, the strategies and mechanisms of inhibiting M1 polarization are poorly explored. This study aims to investigate the role of soluble death receptor 5-Fc (sDR5-Fc) in regulating M1 polarization of macrophages under extreme conditions and explore the mechanisms from the aspect of glycolysis. METHODS: Extreme conditions were induced in RAW264.7 cells. Real-time quantitative polymerase chain reaction and western blot were used to detect the expression of mRNA and proteins, respectively. Cell counting kit-8 was used to investigate the proliferation activity of cells. Expression levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay. RESULTS: We found that sDR5-Fc rescues the proliferation of macrophages under extreme conditions, including nutrition deficiency, excessive peroxide, and ultraviolet irradiation. In addition, administration of sDR5-Fc inhibits the M1 polarization of macrophages induced by lipopolysaccharide (LPS) and interferon-gamma (IFN-γ), as the expression of M1 polarization markers CD86, CXC motif chemokine ligand 10, matrix metalloproteinase 9, and tumor necrosis factor-α, as well as the secretion of inflammatory factors interleukin (IL)-1ß and IL-6, were significantly decreased. By further investigation of the mechanisms, the results showed that sDR5-Fc can recover the LPS and IFN-γ induced pH reduction, lactic acid elevation, and increased expression of hexokinase 2 and glucose transporter 1, which were markers of glycolysis in macrophages. CONCLUSIONS: sDR5-Fc inhibits the M1 polarization of macrophages by blocking the glycolysis, which provides a new direction for the development of strategies in the treatment of myocardial ischemia reperfusion injury.

Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti-inflammatory phenotype through STAT3 pathway.

AIMS: Microglia and infiltrated macrophages play important roles in inflammatory processes after ischemic stroke. Modulating microglia/macrophage polarization from pro-inflammatory phenotype to anti-inflammatory state has been suggested as a potential therapeutic approach in the treatment of ischemic stroke. Melatonin has been shown to be neuroprotective in experimental stroke models. However, the effect of melatonin on microglia polarization after stroke and underlying mechanisms remain unknown. METHODS: In vivo, cerebral ischemia was induced by distal middle cerebral artery occlusion (dMCAO) in C57BL/6J mice. Melatonin was injected intraperitoneally (20 mg/kg) at 0 and 24 hours after ischemia. In vitro, the microglial cell line BV2 was stimulated to the pro-inflammatory state with conditioned media (CM) collected from oxygen-glucose deprivation (OGD) challenged neuronal cell line Neuro-2a (N2a). Real-time PCR was utilized to detect the mRNA expression of microglia phenotype markers. Activation of signal transducer and activator of transcription 3 (STAT3) pathway was determined by Western blot of phosphorylated STAT3 (pSTAT3). A neuron-microglia co-culture system was used to determine whether melatonin can inhibit the neurotoxic effect of pro-inflammatory microglia to post-OGD neurons. RESULTS: Melatonin treatment reduced brain infarct and improved neurological functions 3 days after dMCAO, which was accompanied by decreased expression of pro-inflammatory markers and increased expression of anti-inflammatory markers in the ischemic brain. In vitro studies confirmed that melatonin directly inhibited the pro-inflammatory responses in BV2 cells upon exposure to OGD neuron CM. The microglia possessing pro-inflammatory phenotype exacerbated post-OGD N2a cells death, whereas melatonin reduced such neurotoxic effect. Further, melatonin enhanced the otherwise inhibited pSTAT3 expression in BV2 cells treated with OGD neuron CM. STAT3 blockade significantly reduced the effect of melatonin on microglial phenotype shift. CONCLUSION: Melatonin treatment ameliorates brain damage at least partially through shifting microglia phenotype from pro-inflammatory to anti-inflammatory polarity in a STAT3-dependent manner.