Spinal cord injury (SCI) can cause severe irreversible motor dysfunction and even death. Neural stem cell (NSC) transplantation can promote functional recovery after acute SCI in experimental ...animals, but numerous issues, including low-transplanted cell survival rate, cell de-differentiation, and tumor formation need to be resolved before routine clinical application is feasible. Recent studies have shown that transplanted stem cells facilitate regeneration through release of paracrine factors. Small extracellular vesicles (sEVs), the smallest known membrane-bound nanovesicles, are involved in complex intercellular communication systems and are an important vehicle for paracrine delivery of therapeutic agents. However, the application of NSC-derived small extracellular vesicles (NSC-sEVs) to SCI treatment has not been reported. We demonstrate that NSC-sEVs can significantly reduce the extent of SCI, improve functional recovery, and reduce neuronal apoptosis, microglia activation, and neuroinflammation in rats. Furthermore, our study suggests that NSC-sEVs can regulate apoptosis and inflammatory processes by inducing autophagy. In brief, NSC-sEVs increased the expression of the autophagy marker proteins LC3B and beclin-1, and promoted autophagosome formation. Following NSC-sEV infusion, the SCI area was significantly reduced, and the expression levels of the proapoptotic protein Bax, the apoptosis effector cleaved caspase-3, and the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were significantly reduced, whereas the expression level of the anti-apoptotic protein Bcl-2 was upregulated. In the presence of the autophagy inhibitor 3MA, however, these inhibitory effects of NSC-sEVs on apoptosis and neuroinflammation were significantly reversed. Our results show for the first time that NSC-sEV treatment has the potential to reduce neuronal apoptosis, inhibit neuroinflammation, and promote functional recovery in SCI model rats at an early stage by promoting autophagy.
Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction with high disability and mortality. In recent years, mesenchymal stem cell (MSC)-secreted nano-sized exosomes have shown ...great potential for promoting functional behavioral recovery following SCI. However, MSCs are usually exposed to normoxia in vitro, which differs greatly from the hypoxic micro-environment in vivo. Thus, the main purpose of this study was to determine whether exosomes derived from MSCs under hypoxia (HExos) exhibit greater effects on functional behavioral recovery than those under normoxia (Exos) following SCI in mice and to seek the underlying mechanism.
Electron microscope, nanoparticle tracking analysis (NTA), and western blot were applied to characterize differences between Exos and HExos group. A SCI model in vivo and a series of in vitro experiments were performed to compare the therapeutic effects between the two groups. Next, a miRNA microarray analysis was performed and a series of rescue experiments were conducted to verify the role of hypoxic exosomal miRNA in SCI. Western blot, luciferase activity, and RNA-ChIP were used to investigate the underlying mechanisms.
Our results indicate that HExos promote functional behavioral recovery by shifting microglial polarization from M1 to M2 phenotype in vivo and in vitro. A miRNA array showed miR-216a-5p to be the most enriched in HExos and potentially involved in HExos-mediated microglial polarization. TLR4 was identified as the target downstream gene of miR-216a-5p and the miR-216a-5p/TLR4 axis was confirmed by a series of gain- and loss-of-function experiments. Finally, we found that TLR4/NF-κB/PI3K/AKT signaling cascades may be involved in the modulation of microglial polarization by hypoxic exosomal miR-216a-5p.
Hypoxia preconditioning represents a promising and effective approach to optimize the therapeutic actions of MSC-derived exosomes and a combination of MSC-derived exosomes and miRNAs may present a minimally invasive method for treating SCI.
MicroRNAs and autophagy play critical roles in cardiac hypoxia/reoxygenation (H/R)‐induced injury. Here, we investigated the function of miR‐21 in regulating autophagy and identified the potential ...molecular mechanisms involved. To determine the role of miR‐21 in regulating autophagy, H9c2 cells were divided into the following six groups: control group, H/R group, (miR‐21+ H/R) group, (miR‐21‐negative control + H/R) group, (BEZ235+ H/R) group and (miR‐21+ BEZ235+ H/R) group. The cells underwent hypoxia for 1 hr and reoxygenation for 3 hrs. Cell count kit‐8 was used to evaluate cell function and apoptosis was analysed by Western blotting. Western blotting and transmission electron microscopy were used to investigate autophagy. We found that miR‐21 expression was down‐regulated, and autophagy was remarkably increased in H9c2 cells during H/R injury. Overexpression of miR‐21 with a miR‐21 precursor significantly inhibited autophagic activity and decreased apoptosis, accompanied by the activation of the AKT/mTOR pathway. In addition, treatment with BEZ235, a novel dual Akt/mTOR inhibitor, resulted in a significant increase in autophagy and apoptosis. However, we found that miR‐21‐mediated inhibition of apoptosis and autophagy was partly independent of Akt/mTOR activation, as demonstrated in cells treated with both miR‐21 and BEZ235. We showed that miR‐21 could inhibit H/R‐induced autophagy and apoptosis, which may be at least partially mediated by the Akt/mTOR signalling pathway.
Photonic generation of a phase-coded or frequency-chirped microwave waveform with a tunable microwave carrier frequency using a frequency-tunable optoelectronic oscillator (OEO) is proposed and ...experimentally demonstrated, for the first time to the best of our knowledge. In the proposed system, the tunable OEO has functions to generate a frequency-tunable microwave signal and to output an optical sideband. The optical sideband and a portion of the light wave from the OEO laser source are sent to a polarization modulator (PolM), with their polarization directions aligned with the two principal axes of the PolM. An electrical signal is applied to the PolM, and two complementary phase-coded or frequency-chirped light waves are generated which are converted to an electrical signal by beating the light waves at a high-speed photodetector. The key significance of the technique is that a phase-coded or frequency-chirped microwave waveform with a tunable microwave carrier frequency and a reconfigurable phase-coding or frequency-chirping pattern can be generated without using a separate microwave source. The technique is experimentally verified. The generation of a binary- and a polyphase-coded microwave waveform with a microwave carrier frequency at 10 and 15 GHz is demonstrated. The generation of a linearly frequency-chirped microwave waveform with a chip rate of 20.98 GHz/ns at a 10-GHz carrier frequency and 22.5 GHz/ns at a 15-GHz carrier frequency is also achieved.
Optical vortices, which carry orbital angular momentum (OAM), can be flexibly produced and measured with infrared and visible light. Their application is an important research topic for ...super-resolution imaging, optical communications and quantum optics. However, only a few methods can produce OAM beams in the extreme ultraviolet (XUV) or X-ray, and controlling the OAM on these beams remains challenging. Here we apply wave mixing to a tabletop high-harmonic source, as proposed in our previous work, and control the topological charge (OAM value) of XUV beams. Our technique enables us to produce first-order OAM beams with the smallest possible central intensity null at XUV wavelengths. This work opens a route for carrier-injected laser machining and lithography, which may reach nanometre or even angstrom resolution. Such a light source is also ideal for space communications, both in the classical and quantum regimes.
Measuring the magnetic response of matter relies acutely on the degree to which a magnetic field source’s amplitude, spatial, and temporal character can be tailored. Magnetic fields are inseparable ...from light-matter interaction, yet due to the dominance of electric-field-induced effects in many systems, laser pulses have heretofore provided comparatively limited insight into the high-frequency magnetic response of matter. Conductors or superconductors arranged in a solenoidal configuration embody the state-of-the-art apparatus for generating spatially isolated magnetic fields, but the reliance on electrical circuitry limits the field amplitude, pulse brevity, and absolute timing of the generated fields. We transfer the concept of solenoidal currents commonly leveraged in electromagnets to photo-ionized electrons driven by moderately intense vector laser beams, in a scheme that does not require the laser mode to carry orbital angular momentum. We predict that this all-optical approach will enable magnetic fields exceeding 8 Tesla to be turned on within 50 femtoseconds using moderate laser intensities, an unprecedented combination of parameters that will open the possibility for ultrafast metrological techniques to be combined with intense, spatially isolated, magnetic fields.
Increasing studies have reported that intervertebral disc degeneration (IVDD) is the main contributor and independent risk factor for low back pain (LBP), it would be, therefore, enlightening that ...investigating the exact pathogenesis of IVDD and developing target-specific molecular drugs in the future. Ferroptosis is a new form of programmed cell death characterized by glutathione (GSH) depletion, and inactivation of the regulatory core of the antioxidant system (glutathione system) GPX4. The close relationship of oxidative stress and ferroptosis has been studied in various of diseases, but the crosstalk between of oxidative stress and ferroptosis has not been explored in IVDD. At the beginning of the current study, we proved that Sirt3 decreases and ferroptosis occurs after IVDD. Next, we found that knockout of Sirt3 (Sirt3−/−) promoted IVDD and poor pain-related behavioral scores via increasing oxidative stress-induced ferroptosis. The (immunoprecipitation coupled with mass spectrometry) IP/MS and co-IP demonstrated that USP11 was identified to stabilize Sirt3 via directly binding to Sirt3 and deubiquitinating Sirt3. Overexpression of USP11 significantly ameliorate oxidative stress-induced ferroptosis, thus relieving IVDD by increasing Sirt3. Moreover, knockout of USP11 in vivo (USP11−/−) resulted in exacerbated IVDD and poor pain-related behavioral scores, which could be reversed by overexpression of Sirt3 in intervertebral disc. In conclusion, the current study emphasized the importance of the interaction of USP11 and Sirt3 in the pathological process of IVDD via regulating oxidative stress-induced ferroptosis, and USP11-mediated oxidative stress-induced ferroptosis is identified as a promising target for treating IVDD.
In the NOD-like receptor (NLR) family, the pyrin domain containing 3 (NLRP3) inflammasome is closely related to the progression of atherosclerosis. This study aimed to assess the effects of curcumin ...on NLRP3 inflammasome in phorbol 12-myristate 13-acetate (PMA)-induced macrophages and explore its underlying mechanism.
Human monocytic THP-1 cells were pretreated with curcumin for 1 h and subsequently induced with PMA for 48 h. Total protein was collected for Western blot analysis. Cytokine interleukin (IL)-1β release and nuclear factor kappa B (NF-κB) p65 translocation were detected by ELISA assay and cellular NF-κB translocation kit, respectively.
Curcumin significantly reduced the expression of NLRP3 and cleavage of caspase-1 and IL-1β secretion in PMA-induced macrophages. Moreover, Bay (a NF-κB inhibitor) treatment considerably suppressed the expression of NLRP3 inflammasome in PMA-induced THP-1 cells. Curcumin also markedly inhibited the upregulation of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), phosphorylation level of IκB-α, and activation of NF-κB in PMA-induced macrophages. In addition, purinergic 2X7 receptor (P2X7R) siRNA was administered, and it significantly decreased NLRP3 inflammasome expression in PMA-induced macrophages. Furthermore, curcumin reversed PMA-stimulated P2X7R activation, which further reduced the expression of NLRP3 and cleavage of caspase-1 and IL-1β secretion. Silencing of P2X7R using siRNA also suppressed the activation of NF-κB pathway in PMA-induced macrophages, but P2X7R-silenced cells did not significantly decrease the expression of TLR4 and MyD88.
Curcumin inhibited NLRP3 inflammasome through suppressing TLR4/MyD88/NF-κB and P2X7R pathways in PMA-induced macrophages.
Fe
5
C
2
particle is a promising magnetic material, but there are few reports on pure phase Fe
5
C
2
particle with adjustable morphology. Herein, pure phase Fe
5
C
2
magnetic materials with different ...morphologies were prepared by a simple ethylenediamine carbonization method. This method included the preparation of FeC
2
O
4
·2H
2
O precursors with different morphologies and the co-calcination process of ethylenediamine and the precursors. At the same time, the optimum experimental conditions for the formation of pure phase Fe
5
C
2
particles with different morphologies were investigated. More importantly, the magnetic properties of Fe
5
C
2
particles and the electrocatalytic activities of Fe
5
C
2
particles as electrocatalysts for the hydrogen evolution reaction (HER) are improved by adjusting the morphologies of Fe
5
C
2
particles. The saturation magnetization (
M
s
) and coercivity (
H
c
) of Fe
5
C
2
particle with the cuboid rod-like structure can reach 134.53 emu/g and 305.93 Oe, respectively, demonstrating good soft magnetic properties at 298 K. Simultaneously, the Fe
5
C
2
particle with the porous cuboid rod-like structure exhibits efficient HER activity (225 mV for
j
= − 10 mA cm
−2
). In this work, a simple and generalized Fe
5
C
2
particle synthesis method is proposed, and new explorations are provided for the further applications of Fe
5
C
2
particles with different morphologies in the fields of magnetism and catalysis.
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