Background Cerebral infarction ranks as the second leading cause of disability and death globally, and inflammatory response of glial cells is the main cause of brain damage during cerebral infarction. Methods Studies have shown that mesenchymal stem cells (MSCs) can secrete exosomes and contribute to cerebral disease. Here, we would explore the function of MSC-derived exosome in cerebral infarction. Results Microarray indicated a decrease of miR-542-3p and an increase of Toll-Like Receptor 4 (TLR4) in middle cerebral artery occlusion (MCAO) mice comparing with sham mice. And luciferase and RIP analysis indicated a binding of miR-542-3p and TLR4. Then, we injected AAV9-miR-542-3p into paracele of sham or MCAO mice. Functional analysis showed that AAV9-miR-542-3p inhibited infarction area and the number of degenerating neurons and suppressed inflammatory factors’ expression and inflammatory cell infiltration. As well, transfection of miR-542-3p mimics into HA1800 cells underwent oxygen and glucose deprivation (OGD). Similarly, overexpression of miR-542-3p alleviated OGD induced cell apoptosis, ROS, and activation of inflammation response. Moreover, miR-542-3p could be packaged into MSCs and secreted into HA1800 cells. The extractive exosome-miR-21-3p treatment relieved MCAO- or OGD-induced cerebral injury and inflammation through targeting TLR4. Conclusion These results confirmed that MSC-derived exosome miR-542-3p prevented ischemia-induced glial cell inflammatory response via inhibiting TLR4. These results suggest possible therapeutic strategies for using exosome delivery of miR-542-3p to cure cerebral ischemic injury.

Osteoarthritis (OA) is one of the most common diseases affecting older people; however, there remains no effective targeted drug to combat OA. The aims of this study were (1) to explore the effect of T140 in regulating degeneration of articular cartilage in vivo by targeted blocking of the SDF-1/CXCR4 signaling pathway, and (2) to provide experimental evidence for the development of a novel OA-targeted pharmacotherapy. Thirty-six healthy Hartley guinea pigs were randomly divided into three groups: a T140-treated group (n = 12), a phosphate buffer saline control group (n = 12) and an untreated control group (n = 12). At 2, 4, 6, 8, 10 and 12 weeks of treatment, SDF-1 in serum was quantified by enzyme-linked immunosorbent assay. At 12 weeks of treatment, the cartilage from knee tibial plateau in the knee joint was collected for H&E, Safranin-O staining and Mankin grading; measurement for mRNA levels of matrix metalloproteinases (MMP-3, MMP-9 and MMP-13), aggrecan (ACAN) and collagen II (Col II) using RT-PCR; and measurement for Col II protein levels by western blot. Results showed that SDF-1 in serum increased in the T140 group and increased in the control groups. H&E and Safranin-O staining revealed less cartilage loss in T140-treated animals compared to controls. The mRNA levels of MMP-3, MMP-9 and MMP-13 in cartilage were much lower in the T140 group than other groups, but mRNA levels of ACAN and Col II in cartilage were higher in the T140-treated group. Col II protein levels in the T140 group and control groups were different. T140 can downregulate the expression of matrix-degrading enzyme and lessen the degeneration of cartilage by blocking the SDF-1/CRCR4 signaling pathway in vivo. This mechanism may present a pharmacological target for the treatment of OA.

Microglia are the resident immune cells in the central nervous system and play an essential role in brain homeostasis and neuroprotection in brain diseases. Exosomes are crucial in intercellular communication by transporting bioactive miRNAs. Thus, this study aimed to investigate the function of microglial exosome in the presence of ischemic injury and related mechanism. Oxygen-glucose deprivation (OGD)-treated neurons and transient middle cerebral artery occlusion (TMCAO)-treated mice were applied in this study. Western blotting, RT-PCR, RNA-seq, luciferase reporter assay, transmission electron microscope, nanoparticle tracking analysis, immunohistochemistry, TUNEL and LDH assays, and behavioral assay were applied in mechanistic and functional studies. The results demonstrated that exosomes derived from microglia in M2 phenotype (BV2-Exo) were internalized by neurons and attenuated neuronal apoptosis in response to ischemic injury in vitro and in vivo . BV2-Exo also decreased infarct volume and behavioral deficits in ischemic mice. Exosomal miRNA-137 was upregulated in BV2-Exo and participated in the partial neuroprotective effect of BV2-Exo. Furthermore, Notch1 was a directly targeting gene of exosomal miRNA-137. In conclusion, these results suggest that BV2-Exo alleviates ischemia-reperfusion brain injury through transporting exosomal miRNA-137. This study provides novel insight into microglial exosomes-based therapies for the treatment of ischemic brain injury.

Background: To explore the location accuracy and early clinical outcomes of using a 3D-printed individualized navigation template to assist in the reconstruction of the anterior cruciate ligament (ACL).Methods: A single center randomized control study was conducted. Patients with ACL injury were treated with a conventional operation or an operation assisted by a 3D-printed individualized navigation template (the 3D group). The primary endpoint was the accuracy of the actual reconstruction compared with the planned position.Results: There were 20 and 23 participants in the conventional group and the 3D group, respectively. There were no differences in the bone tunnel position between the actual postoperative position and the preoperative design in the 3D group (P>0.05). Compared with the 3D group, the positioning of the femoral tunnel was more inferior and shallower in the conventional group (P<0.05). The position of the tibia tunnel was closer to the anterior and medial edge of the tibial platform in the conventional group compared to the 3D group (P<0.05). The intraoperative positioning time was shorter in the 3D group than in the conventional group (3.3±1.0 vs. 5.9±1.8 minutes, P<0.001). The Lysholm and International Knee Documentation Committee scores did not differ between the two groups (P>0.05 for both), and all patients improved after surgery (P<0.001). Conclusions:The 3D-printed individualized navigation template showed good location accuracy and resulted in reduced intraoperative positioning time compared to the traditional method for ACL reconstruction.

Osteoarthritis (OA) is an aseptic inflammatory disease which is associated with the stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) axis. Accumulating studies have identified numbers of microRNAs (miRNAs) that serve important roles in the pathogenesis of OA. However, whether and how the inhibition of the SDF-1/CXCR4 axis induces alterations in miRNA expression remains largely unclear. miRNA profiling was performed in OA chondrocytes stimulated with SDF-1 alone, or SDF-1 with the CXCR4 antagonist TN14003 by miRNA microarray. Candidate miRNAs were verified by reverse transcription quantitative polymerase chain reaction. Bioinformatic analyses including target prediction, gene ontology (GO) and pathway analysis were performed to explore the potential functions of candidate miRNAs. Notably, 7 miRNAs (miR-146a-5p, miR-221-3p, miR-126-3p, miR-185-5p, miR-155-5p, miR-124-3p and miR-130a-3p) were significantly differentially expressed. GO analysis indicated that miR-146a-5p and its associated genes were enriched in receptor regulatory activity, nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase activity, cellular response to interleukin-1, cytokine-cytokine receptor interaction, NF-κB signaling pathway and osteoclast differentiation pathways. CXCR4 was predicted to be a target of miR-146a-5p with high importance. The mRNA and protein levels of key factors involved in cartilage degeneration were measured following manipulation of the expression levels of miR-146a-5p in OA chondrocytes. CXCR4 and MMP-3 levels were negatively associated with miR-146a-5p expression, while the levels of type II collagen and aggrecan were positively associated. These data reveal that TN14003 upregulates miR-146a-5p expression, and also pinpoints a novel role of miR-146a-5p in inhibiting cartilage degeneration by directly targeting the SDF-1/CXCR4 axis.

ABSTRACT:The oxidative chemical polymerization of 3, 4-ethylenedioxythiophene (EDOT) was conducted at room temperature in the presence of poly(styrene sulfonate) (PSS) as the doping agent, sodium supersulphate (Na 2 S 2 O 8 ) and ferric sulphate(Fe 2 (SO 4 ) 3 ) as the compound oxidant and deionized water as the solvent. In order to remove sodium ion (Na þ ), ferric ion (Fe 3þ ), and sulfate ion (SO4 2À ), certain amount of ion exchanger was added after 24 h, the dark blue poly(3, 4-ethylenedioxythiophene) (PEDT)/PSS solution was obtained. The influence of different proportions of EDOT and PSS, different proportions of EDOT and the compound oxidant, different stirring rates on the morphology, and surface resistivity were discussed. The influence of pH value of the PEDT/PSS solution, the coating thickness, and soak time on the surface resistivity was investigated. Recipe and experimental conditions were optimized and the PEDT/PSS solution was obtained with excellent performance which has relatively low in surface resistance, good water tolerance, and light transmittance.

Background Interleukin-1β (IL-1)-treated mesenchymal stem cells (MSCs) and IL-1-MSCs-conditioned medium (CM) exert anti-inflammatory roles. Astrocytes are essential for the modulation of synaptic activity and neuronal homeostasis in the brain. Exosomes are the critical mediators in intercellular communication. However, the mechanism underlying the anti-inflammatory effect of IL-1-treated MSCs remains unknown. Methods In this study, exosomes (IL-1-Exo) were isolated from IL-1-treated MSCs. In addition, lipopolysaccharide (LPS)-treated hippocampal astrocytes and status epilepticus (SE) mice were treated with IL-1-Exo. Inflammatory activity, astrogliosis, and cognitive performance were measured to determine the effect of IL-1-Exo on inflammation. Results The results revealed that IL-1-Exo significantly inhibited LPS-induced astrogliosis and inflammatory responses of astrocytes. Also, IL-1-Exo reversed the LPS-induced effect on calcium signaling. The Nrf2 signaling pathway was associated with the effect of IL-1-Exo in LPS-treated astrocytes. Furthermore, IL-1-Exo reduced the inflammatory response and improved the cognitive performance of SE mice. Conclusion The results suggest that IL-1-Exo inhibited LPS-induced inflammatory responses in astrocytes and SE mice and that the effect of IL-1-Exo was primarily mediated through the Nrf-2 signaling pathway. This study provides a new understanding of the molecular mechanism of inflammation-associated brain diseases and an avenue to develop nanotherapeutic agents for the treatment of inflammatory conditions in the brain.

Shuang Huang Lian Injection (SHLI) has been used in China for over 30 years as an effective and widely used Chinese herbal prescription to treat acute respiratory infectious. SHLI has, however, caused many severe anaphylactoid reactions. It is important to identify the potential anaphylactoid components of SHLI. Spectrum-effect relationships were used to explore potentially anaphylactoid components. Based on the original herbal formula, honeysuckle, Fructus Forsythiae and Radix Scutellariae extracts were prepared and combined in appropriate proportions. The preparations were then injected into the caudal vein of rats to obtain in vivo serum samples for pharmacological evaluation and fingerprint analysis. The release rate of β-hexosaminidase from RBL-2H cells and plasma histamine level was used as the pharmacological index. Chromatographic fingerprint analysis identified 22 common peaks. Regression analysis and correlation analysis were used to calculate the relationships between the peaks and the pharmacological effects and identified peaks 5, 6, 11, 12 and 17 as likely anaphylactoid agents. The correlated peaks were identified by comparing the fingerprints with in vitro samples and reference standard samples and the structure was identified by UPLC-TOF-MS. This study established a prospective method to clarify the anaphylactoid components in SHLI, which would provide guidances for screening anaphylactoid components in other traditional Chinese medicine injections.