Administration of exosomes derived from mesenchymal stromal cells (MSCs) could improve some neurologic conditions by transferring functional biomolecules to recipient cells. Furthermore, exosomes ...from hypoxic progenitor cells exerted better therapeutic effects in organ injury through specific cargoes. However, there are no related reports about whether exosomes derived from MSCs or hypoxia‐preconditioned MSCs (PC‐MSCs) could prevent memory deficits in Alzheimer disease (AD). In this study, the exosomes derived from MSCs or PC‐MSCs were systemically administered to transgenic APP/PS1 mice. The expression of miR‐21 in MSCs was significantly increased after hypoxic treatment. Injection of exosomes from normoxic MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aβ levels in the brain; could decrease the activation of astrocytes and microglia; could down‐regulate proinflammatory cytokines (TNF‐α and IL‐1β); and could up‐regulate anti‐inflammatory cytokines (IL‐4 and ‐10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF‐κB. Compared to the group administered exosomes from normoxic MSCs, in the group administered exosomes from PC‐MSCs, learning and memory capabilities were significantly improved; the plaque deposition and Aβ levels were lower, and expression of growth‐associated protein 43, synapsin 1, and IL‐10 was increased; and the levels of glial fibrillary acidic protein, ionized calcium‐binding adaptor molecule 1, TNF‐α, IL‐1β, and activation of STAT3 and NF‐κB were sharply decreased. More importantly, exosomes from PC‐MSCs effectively increased the level of miR‐21 in the brain of AD mice. Additionally, replenishment of miR‐21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features. Taken together, these findings suggest that exosomes from PC‐MSCs could improve the learning and memory capabilities of APP/PS1 mice, and that the underlying mechanism may lie in the restoration of synaptic dysfunction and regulation of inflammatory responses through regulation of miR‐21.—Cui, G.‐H., Wu, J., Mou, F.‐F., Xie, W.‐H., Wang, F.‐B., Wang, Q.‐L., Fang, J., Xu, Y.‐W., Dong, Y.‐R., Liu, J.‐R., Guo, H.‐D. Exosomes derived from hypoxia‐preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB J. 32, 654–668 (2018). www.fasebj.org
Exosomes are lipid-bilayer enclosed nano-sized vesicles that transfer functional cellular proteins, mRNA and miRNAs. Mesenchymal stem cells (MSCs) derived exosomes have been demonstrated to prevent ...memory deficits in the animal model of Alzheimer's disease (AD). However, the intravenously injected exosomes could be abundantly tracked in other organs except for the targeted regions in the brain. Here, we proposed the use of central nervous system-specific rabies viral glycoprotein (RVG) peptide to target intravenously-infused exosomes derived from MSCs (MSC-Exo) to the brain of transgenic APP/PS1 mice. MSC-Exo were conjugated with RVG through a DOPE-NHS linker.
RVG-tagged MSC-Exo exhibited improved targeting to the cortex and hippocampus after being administered intravenously. Compared with the group administered MSC-Exo, in the group administered RVG-conjugated MSC-Exo (MSC-RVG-Exo) plaque deposition and Aβ levels were sharply decreased and activation of astrocytes was obviously reduced. The brain targeted exosomes derived from MSCs was better than unmodified exosomes to improve cognitive function in APP/PS1 mice according to Morris water maze test. Additionally, although MSC-Exo injected intravenously reduced the expression of pro-inflammatory mediators TNF-α, IL-β, and IL-6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSC-RVG-Exo significantly reduced the levels of TNF-α, IL-β, and IL-6 while significantly raised the levels of IL-10, IL-4 and IL-13.
Taken together, our results demonstrated a novel method for increasing delivery of exosomes for treatment of AD. By targeting exosomes to the cortex and hippocampus of AD mouse, there was a significant improvement in learning and memory capabilities with reduced plaque deposition and Aβ levels, and normalized levels of inflammatory cytokines.
Objective
Reliable electrophysiological indicators are urgently needed in the precise evaluation of Parkinson’s disease (PD). It is still elusive whether oculomotor performance is impaired or has ...clinical value in early PD. This study aims to explore oculomotor performance in newly diagnosed, drug-naïve PD and its correlation with clinical phenotype.
Methods
Seventy-five patients with
de novo
PD, 75 patients with essential tremor (ET), and 46 gender-and age-matched healthy controls (HCs) were included in this cross-sectional study. All subjects underwent oculomotor test
via
videonystagmography. Visually guided saccade latency, saccadic accuracy and gain in smooth pursuit eye movement (SPEM) at three frequencies of the horizontal axis were compared among the three groups. Patients with PD also received detailed motor and non-motor evaluation by serial scales. The association between key oculomotor parameters and clinical phenotypes were explored in PD patients.
Results
Both
de novo
PD and ET patients showed prolonged saccadic latency and decreased saccadic accuracy relative to HCs. SPEM gain in PD was uniformly reduced at each frequency. SPEM gain at 0.4 Hz was also decreased in ET compared with HCs. However, there was no significant difference of oculomotor parameters between
de novo
PD and ET patients. Furthermore, prolonged saccadic latency was correlated with long disease duration, whereas decreased SPEM gain was associated with severe motor symptoms in
de novo
PD patients.
Conclusion
Ocular movements are impaired in
de novo
, drug naïve PD patients; these changes could be indicators for disease progression in PD.
Accumulating evidence suggests that freezing of gait (FOG) is a unique gait disturbance in Parkinson’s disease (PD), and its pathophysiology is not fully elucidated. The present study aims to ...investigate the clinical and oculomotor associations with FOG in Chinese PD patients. From Jan 2017 to Dec 2019, a total of 210 PD patients were consecutively registered for FOG evaluation based on item-3 of the Freezing of Gait Questionnaire (FOGQ). We explored the demographic, motor and non-motor symptom differences in FOG positive (PD+FOG, n=45) versus negative (PD-FOG, n=165) group. In addition, 40 PD patients and 37 healthy controls (HC) also underwent oculomotor test via videonystagmography (VNG). Visually guided saccade latency, saccade accuracy and gain in smooth pursuit eye movement (SPEM) at three frequencies of horizontal axis were compared among PD+FOG(n=20), PD-FOG(n=20) and HC(n=37). Compared with PD-FOG, PD+FOG had longer disease duration, more severe motor symptoms, lower cognitive scores, more severe depressive and autonomic impairments, as well as higher daily levodopa equivalent dosage. FOG occurred more frequently in patients with wearing-off. VNG subgroup analysis demonstrated that PD+FOG had prolonged saccade latency and decreased saccade accuracy relative to PD-FOG or HC. SPEM gain at 0.1HZ and 0.2 Hz was also decreased in PD+FOG compared with HC. Furthermore, prolonged saccade latency was correlated with higher FOGQ scores in PD patients. Our results verify that PD with FOG patients suffer from more severe motor and non-motor symptoms, indicating more extensive neurodegeneration. Prolonged saccade latency could be a practical oculomotor parameter both for identification and progression of FOG in PD.
As possible candidate screening instruments for benign paroxysmal positional vertigo (BPPV), studies to validate the Dizziness Handicap Inventory (DHI) sub-scale (5-item and 2-item) and total scores ...are rare in China. From May 2014 to December 2014, 108(55 with and 53 without BPPV) patients complaining of episodic vertigo in the past week from a vertigo outpatient clinic were enrolled for DHI evaluation, as well as demographic and other clinical data. Objective BPPV was subsequently determined by positional evoking maneuvers under the record of optical Frenzel glasses. Cronbach’s coefficient
α
was used to evaluate the reliability of psychometric scales. The validity of DHI total, 5-item and 2-item questionnaires to screen for BPPV was assessed by receiver operating characteristic (ROC) curves. It revealed that the DHI 5-item questionnaire had good internal consistency (Cronbach’s coefficient
α
= 0.72). Area under the curve of total DHI, 5-item and 2-item scores for discriminating BPPV from those without was 0.678 (95 % CI 0.578–0.778), 0.873(95 % CI 0.807–0.940) and 0.895(95 % CI 0.836–0.953), respectively. It revealed 74.5 % sensitivity and 88.7 % specificity in separating BPPV and those without, with a cutoff value of 12 in the 5-item questionnaire. The corresponding rate of sensitivity and specificity was 78.2 and 88.7 %, respectively, with a cutoff value of 6 in 2-item questionnaire. The present study indicated that both 5-item and 2-item questionnaires in the Chinese version of DHI may be more valid than DHI total score for screening objective BPPV and merit further application in clinical practice in China.
Sciatic nerve injury is a common disease of peripheral nerve in clinic. After nerve injury, there are many dysfunctions in motoneurons and muscles following regeneration. Previous studies mostly ...investigated the aspects related to the injured nerve, and the effect on the recurrent inhibition (RI) pathway of spine following regeneration was not fully understood. Following reinnervation after temporary sciatic nerve crush, the functional alteration of RI was studied. In adult rats, RI between lateral gastrocnemius-soleus (LG-S) and medial gastrocnemius (MG) motor pools was assessed by conditioning monosynaptic reflexes (MSRs) elicited from the cut dorsal roots and recorded from either the LG-S or MG nerves by antidromic stimulation of the synergist muscle nerve. The following results were obtained. (1) The RI of MSRs in rats was almost lost (<5 weeks) after sciatic nerve crush. Although the RI partially recovered following reinnervation (6 weeks), it remained permanently depressed (up to 14 weeks). (2) Sciatic
In this study, in order to investigate the influence of Cr element on the impact fracture process of ductile Ni-resistant alloyed iron at low temperature, different contents of Cr element were added ...to ductile Ni-resistant （DNR） austenitic alloyed iron. The experimental results show that Cr addition can increase the hardness of the DNR alloyed iron, but it has an destructive effect on low-temperature impact properties. Through the analysis of the dynamic load and absorbed energy of samples with different Cr contents in the impact fracture process, and the comparison of the impact fracture process at room and low temperatures, it reveals that Cr addition into the DNR alloyed iron can facilitate the formation of the carbide mixture in Mn23C6 and Cr23C6 with homogeneous and discontinuous distribution. Meanwhile, Cr addition also can improve the the maximum dynamic load and crack initiation energy at low temperature, but has no obvious effect on the yield behavior of the DNR alloyed iron in the impact fracture process. Compared with the impact crack propagation process at room temperature, the metastable propagation energy at low temperature declines significantly with an increase in Cr content. This is because the micro-cracks that caused by the carbides weaken the matrix, resulting in the decline of impact crack propagation resistance. The fracture analysis results also show that the impact fracture mechanism gradually transforms from ductile to brittle with an increase in Cr content at low temperature. It explains that too much Cr addition can lead to brittle fracture even though the austenitic matrix has a good toughness at low temperature.
Cementites decomposition of a pearlitic ductile cast iron during graphitization annealing heat treatment was investigated.Fractographies and microstructures of heat treated samples were observed ...using a scanning electron microscope and mechanical properties were measured by a universal tensile test machine.The results indicated that during isothermal annealing at 750°C,the tensile strength of pearlitic ductile cast iron was increased to a peak value at 0.5h,and decreased gradually thereafter but the elongation was enhanced with the increase of annealing time.Moreover,the diffusion coefficient of carbon atoms could be approximately calculated as 0.56μm2/s that could be regarded as the shortrange diffusion.As the holding time was short(0.5h),diffusion of carbon atoms was incomplete and mainly occurred around the graphites where the morphology of cementites changed from fragmentized shape to granular shape.In addition,the ductile cast iron with tensile strength of 740MPa and elongation of 7% could be achieved after graphitization annealing heat treatment for 0.5h.Two principal factors should be taken into account.First,the decomposition of a small amount of cementites was beneficial for increasing the ductility up to elongation of 7%.Second,the diffusion of carbon atoms from cementites to graphites could improve the binding force between graphites and matrix,enhancing the tensile strength to 740 MPa.
Cementites decomposition of a pearlitic ductile cast iron during graphitization annealing heat treatment was investigated.Fractographies and microstructures of heat treated samples were observed ...using a scanning electron microscope and mechanical properties were measured by a universal tensile test machine.The results indicated that during isothermal annealing at 750°C,the tensile strength of pearlitic ductile cast iron was increased to a peak value at 0.5h,and decreased gradually thereafter but the elongation was enhanced with the increase of annealing time.Moreover,the diffusion coefficient of carbon atoms could be approximately calculated as 0.56μm2/s that could be regarded as the shortrange diffusion.As the holding time was short（0.5h）,diffusion of carbon atoms was incomplete and mainly occurred around the graphites where the morphology of cementites changed from fragmentized shape to granular shape.In addition,the ductile cast iron with tensile strength of 740MPa and elongation of 7% could be achieved after graphitization annealing heat treatment for 0.5h.Two principal factors should be taken into account.First,the decomposition of a small amount of cementites was beneficial for increasing the ductility up to elongation of 7%.Second,the diffusion of carbon atoms from cementites to graphites could improve the binding force between graphites and matrix,enhancing the tensile strength to 740 MPa.
Current approaches to fabrication of nSC composites for bone tissue engineering (BTE) have limited capacity to achieve uniform surface functionalization while replicating the complex architecture and ...bioactivity of native bone, compromising application of these nanocomposites for in situ bone regeneration. A robust biosilicification strategy is reported to impart a uniform and stable osteoinductive surface to porous collagen scaffolds. The resultant nSC composites possess a native‐bone‐like porous structure and a nanosilica coating. The osteoinductivity of the nSC scaffolds is strongly dependent on the surface roughness and silicon content in the silica coating. Notably, without the use of exogenous cells and growth factors (GFs), the nSC scaffolds induce successful repair of a critical‐sized calvarium defect in a rabbit model. It is revealed that topographic and chemical cues presented by nSC scaffolds could synergistically activate multiple signaling pathways related to mesenchymal stem cell recruitment and bone regeneration. Thus, this facile surface biosilicification approach could be valuable by enabling production of BTE scaffolds with large sizes, complex porous structures, and varied osteoinductivity. The nanosilica‐functionalized scaffolds can be implanted via a cell/GF‐free, one‐step surgery for in situ bone regeneration, thus demonstrating high potential for clinical translation in treatment of massive bone defects.
A biosilicification strategy is developed to provide a uniform and robust osteoinductive surface on porous natural collagen scaffolds. The resultant nanosilica–collagen (nSC) scaffolds possess topographical and chemical cues for superior in situ bone defect repair, without the use of exogenous cells or growth factors. This novel preparation of biomimetic bone scaffolds shows promising clinical applications in the treatment of bone defects.
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