Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus that affects approximately half of patients with diabetes. Current treatment regimens cannot treat DPN effectively. ...Schwann cells (SCs) are very sensitive to glucose concentration and insulin, and closely associated with the occurrence and development of type 1 diabetic mellitus (T1DM) and DPN. Apoptosis of SCs is induced by hyperglycemia and is involved in the pathogenesis of DPN. This review considers the pathological processes of SCs apoptosis under high glucose, which include the following: oxidative stress, inflammatory reactions, endoplasmic reticulum stress, autophagy, nitrification and signaling pathways (PI3K/AKT, ERK, PERK/Nrf2, and Wnt/β-catenin). The clarification of mechanisms underlying SCs apoptosis induced by high glucose will help us to understand and identify more effective strategies for the treatment of T1DM DPN.
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Summary
A nitrogen‐doped carbon coated subglobose Na3V2(PO4)2F3@C (NVPF) cathode for sodium‐ion batteries was synthesized by using hexadecyl trimethyl ammonium bromide (CTAB) as soft template and ...polyvinylidene fluoride (PVDF) as carbon source. CTAB plays a significant role on the formation of sphere micelles. Precursor ions are self‐assembled on the surface at appropriate concentration and its mechanism is investigated in subglobose NVPF@C‐4. CTAB also increases the conductivity of carbon layer as −(CH3)3N+ in CTAB is combined with residual carbon from PVDF to form partially N‐doped carbon. Meanwhile, the carbon source PVDF contributes to prevent the generation of impurity Na3V2(PO4)3 by compensating the evaporative fluorine. Generally, CTAB and PVDF play multifunctional roles in regulating Na3V2(PO4)2F3@C cathode with well‐developed crystallite, high rate performance, good conductivity, and ultra‐long cycle life. The specific capacity of NVPF@C‐4 cathode at 0.1 C and 10 C is as high as 121.5 mAh·g−1 and 99.2 mAh·g−1 with high capacity retention of 90.1% even after 1000 cycles at 10 C. The excellent rate performance is also attributed to the high diffusion coefficient of Na+ and high exchange current according to the kinetic analysis. The enhanced electrochemical performances reveal the special regulation in this paper is feasible to obtain excellent structural stability of NVPF materials.
Spherical micelles are formed through the regular arrangement of hydrophobic long carbon chain (C16H33−) and hydrophilic trimethylamine (−(CH3)3N+) of CTAB. The hydrophobic PVDF are homogeneously dispersed in the aqueous solution under the dispersing role of CTAB. Through the self‐assembled of precursor anions (PO43−, F−) and cations (Na+, V3+) on the surface of micelle, subglobose Na3V2(PO4)3F3 cathode for sodium‐ion batteries with well‐developed crystallite, ultra‐long cycle life and high rate performance are constructed after the sintering process.
Notoginsenoside R1 (NGR1) is the main monomeric component extracted from the dried roots and rhizomes of Panax notoginseng, and exerts pharmacological action against myocardial infarction (MI). Owing ...to the differences in compound distribution, absorption, and metabolism
in vivo
, exploring a more effective drug delivery system with a high therapeutic targeting effect is crucial. In the early stages of MI, CD11b-expressing monocytes and neutrophils accumulate at infarct sites. Thus, we designed a mesoporous silica nanoparticle-conjugated CD11b antibody with loaded NGR1 (MSN-NGR1-CD11b antibody), which allowed NGR1 precise targeted delivery to the heart in a noninvasively manner. By increasing targeting to the injured myocardium, intravenous injection of MSN-NGR1-CD11b antibody nanoparticle in MI mice improved cardiac function and angiogenesis, reduced cell apoptosis, and regulate macrophage phenotype and inflammatory factors and chemokines. In order to further explore the mechanism of NGR1 protecting myocardium, cell oxidative stress model and oxygen-glucose deprivation (OGD) model were established. NGR1 protected H9C2 cells and primary cardiomyocytes against oxidative injury induced by H
2
O
2
and OGD treatment. Further network pharmacology and molecular docking analyses suggested that the AKT, MAPK and Hippo signaling pathways were involved in the regulation of NGR1 in myocardial protection. Indeed, NGR1 could elevate the levels of
p
-Akt and
p
-ERK, and promote the nuclear translocation of YAP. Furthermore, LY294002 (AKT inhibitor), U0126 (ERK1/2 inhibitor) and Verteporfin (YAP inhibitor) administration in H9C2 cells indicated the involvement of AKT, MAPK and Hippo signaling pathways in NGR1 effects. Meanwhile, MSN-NGR1-CD11b antibody nanoparticles enhanced the activation of AKT and MAPK signaling pathways and the nuclear translocation of YAP at the infarcted site. Our research demonstrated that MSN-NGR1-CD11b antibody nanoparticle injection after MI enhanced the targeting of NGR1 to the infarcted myocardium and improved cardiac function. More importantly, our pioneering research provides a new strategy for targeting drug delivery systems to the ischemic niche.
NGR1 protected H9C2 cells and primary cardiomyocytes against oxidative injury induced by H
2
O
2
and OGD treatment. MSN-NGR1-CD11b antibody nanoparticle injection after MI enhanced the targeting of NGR1 to the infarcted myocardium and improved cardiac function by activating PIK3/AKT, MAPK/ERK and YAP signaling pathways.
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CD11b antibody modification enhanced the target of Mesoporous silica nanoparticles to injured myocardium.
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NGR1 promoted the survival of H9C2 against oxidative stress injury through PIK3/AKT, MAPK/ERK and YAP signaling pathways.
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NGR1 protected neonatal and adult cardiomyocytes from H
2
O
2
and OGD induced oxidative stress damage.
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MSN-NGR1-CD11b antibody nanoparticles improved heart function by activating PIK3/AKT, MAPK/ERK and YAP signaling pathways.
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MSN-NGR1-CD11b antibody nanoparticles induced M2 polarization of macrophages and regulated the inflammatory factors.
Accumulating evidence shows that large tumor suppressor 1 (LATS1) as a novel resident governor of cellular homeostasis is implicated in multiple tumorigenic properties including cell growth, ...apoptosis and metastasis. However, the contribution of LATS1 to gastric carcinoma (GC) remains unclear. The correlation of LATS1 expression with clinicopathologic characteristics, GC prognosis and recurrence was analyzed by immunohistochemistry, Univariate and Kaplan-Meier analysis. Functional experiments were performed to investigate biological behaviors of GC cells and underlying molecular mechanisms. Tumor growth and metastasis was assessed in vivo using orthotopic implantation GC models in severe combined immune deficiency (SCID) mice. Consequently, decreased LATS1 expression was significantly associated with the lymph node metastasis, poor prognosis and recurrence. Ectopic expression of LATS1 decreased GC cell proliferation and invasion in vitro and inhibited tumor growth and liver metastasis in vivo, but depletion of LATS1 expression restored the invasive phenotype. Further observation indicated that YAP pathway was required for LATS1-induced inhibition of cell growth and invasion, and LATS1 restrained nuclear transfer of YAP, downregulated YAP, PCNA, CTGF, MMP-2, MMP-9, Bcl-2 and CyclinD1 expression and upregulated p-YAP and Bax expression. Our findings suggest that LATS1 is a potential candidate tumor suppressor and inhibits the growth and metastasis of GC cells via downregulation of the YAP signaling.
●LiMn0.8Fe0.2PO4/C nanocrystal is synthesized by a facile solvothermal reaction.●Melamine is used as a nitrogen source of N-doped carbon coated LiMn0.8Fe0.2PO4/C.●The transformation law of morphology ...from nanosheet to nanoparticle is studied.●The positive effect of N atoms on the electrochemical performance is illustrated.●Particle-like LMFP-7 delivers excellent cycling performance and chemical stability.
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N-doped carbon coated LiMn0.8Fe0.2PO4 nanocrystal for lithium-ion batteries was prepared by a facile solvothermal method. The doping effect of nitrogen is regulated by altering the addition amount of nitrogen source melamine. Result shows that the introduction of N atoms does not change the crystal structure of LiMn0.8Fe0.2PO4/C. The ‒NH2 functional groups in melamine can react with the ‒OH groups in pyrolytic carbon generated by the pre-sintering of sucrose. Then, multiple nanosheets in LMFP-0 are combined together and the morphology of LiMn0.8Fe0.2PO4/C is transformed to nano particle-like in LMFP-7. The doped nitrogen in the forms of pyridinic, pyrrolic and graphitic N are derived from the combination of pyrolytic carbon and melamine, which can generate active defective sites and improve the electronic conductivity and diffusion rate of lithium ions. Sample LMFP-7 delivers the best electrochemical performance with a capacity of 154.7, 144.2 and 110.0 mA h g−1 at 0.1, 1 and 5 C, respectively. The LiMn0.8Fe0.2PO4/C cathode exhibits good electrochemical reversibility, low charge transfer resistance (46.9 Ω) and high diffusion coefficient (1.35 × 10−13 cm2 s−1). It also delivers excellent cyclic performance, structural stability and chemical stability.
Growing evidence indicates that electroacupuncture (EA) has a definite effect on the treatment of peripheral nerve injury (PNI), but its mechanism is not completely clear. miRNAs are involved in the ...regulation of a variety of biological processes, and EA may enhance PNI repair by regulating miRNAs. In this study, the rat sciatic nerve injury model was treated with EA for 4 weeks. Acupoints Huantiao (GB30) and Zusanli (ST36) were stimulated by EA 20 minutes once a day, 6 days a week for 4 weeks. We found that EA treatment down-regulated the expression of miR-1b in the local injured nerve. In vitro experiments showed that overexpression of miR-1b inhibited the expression of brain derived neurotrophic factor (BDNF) in rat Schwann cells (SCs) line while BDNF knockdown inhibited the proliferation, migration and promoted apoptosis of SCs. Subsequently, the rat model of sciatic nerve injury was treated by EA treatment and injection of agomir-1b or antagomir-1b. The nerve conduction velocity ratio (NCV), sciatic functional index (SFI) and S100 immunofluorescence staining were examined and showed that compared with the model group, NCV, SFI, proliferation of SC and expression of BDNF in the injured nerves of rats treated with EA or EA + anti-miR-1b were elevated, while EA+miR-1b were reduced, indicating that EA promoted sciatic nerve function recovery and SCs proliferation through down-regulating miR-1b. To summarize, EA may promote the proliferation, migration of SC and nerve repair after PNI by regulating miR-1b which targets BDNF.
Purpose. Our study is aimed at investigating the mechanism by which electroacupuncture (EA) promoted nerve regeneration by regulating the release of exosomes and exosome-mediated miRNA-21 (miR-21) ...transmission. Furthermore, the effects of Schwann cells- (SC-) derived exosomes on the overexpression of miR-21 for the treatment of PNI were investigated. Methods. A sciatic nerve injury model of rat was constructed, and the expression of miR-21 in serum exosomes and damaged local nerves was detected using RT-qPCR after EA treatment. The exosomes were identified under a transmission electron microscope and using western blotting analysis. Then, the exosome release inhibitor, GW4869, and the miR-21-5p-sponge used for the knockdown of miR-21 were used to clarify the effects of exosomal miR-21 on nerve regeneration promoted by EA. The nerve conduction velocity recovery rate, sciatic nerve function index, and wet weight ratio of gastrocnemius muscle were determined to evaluate sciatic nerve function recovery. SC proliferation and the level of neurotrophic factors were assessed using immunofluorescence staining, and the expression levels of SPRY2 and miR-21 were detected using RT-qPCR analysis. Subsequently, the transmission of exosomal miR-21 from SC to the axon was verified in vitro. Finally, the exosomes derived from the SC infected with the miR-21 overexpression lentivirus were collected and used to treat the rat SNI model to explore the therapeutic role of SC-derived exosomes overexpressing miR-21. Results. We found that EA inhibited the release of serum exosomal miR-21 in a PNI model of rats during the early stage of PNI, while it promoted its release during later stages. EA enhanced the accumulation of miR-21 in the injured nerve and effectively promoted the recovery of nerve function after PNI. The treatment effect of EA was attenuated when the release of circulating exosomes was inhibited or when miR-21 was downregulated in local injury tissue via the miR-21-5p-sponge. Normal exosomes secreted by SC exhibited the ability to promote the recovery of nerve function, while the overexpression of miR-21 enhanced the effects of the exosomes. In addition, exosomal miR-21 secreted by SC could promote neurite outgrowth in vitro. Conclusion. Our results demonstrated the mechanism of EA on PNI from the perspective of exosome-mediated miR-21 transport and provided a theoretical basis for the use of exosomal miR-21 as a novel strategy for the treatment of PNI.
Objective:
The aim of this study was to explore the role and mechanisms of electroacupuncture (EA) in the regulation of chemokines in endogenous stem cell mobilization and myocardial regeneration ...after myocardial infarction (MI).
Methods:
An MI model was constructed in adult male Sprague-Dawley rats by ligating the left anterior descending coronary artery. After 4 weeks of treatment, echocardiography was used to detect changes in cardiac function, and Masson’s trichrome staining was used to detect collagen deposition. In addition, immunofluorescence staining was applied to examine von Willebrand factor (vWF)-positive vessels, the expression of cardiac troponin T (cTnT) and proliferation marker Ki67, and the number of c-kit-positive, C-X-C chemokine receptor type 4 (CXCR4)-positive, and Sca-1-positive endogenous stem cells in the infarcted area. In addition, the expression of stromal cell-derived factor (SDF)-1 and stem cell factor (SCF) was detected.
Results:
EA increased the ejection fraction after MI, reduced collagen deposition and cellular apoptosis, and increased the number of blood vessels compared with an untreated model group. EA significantly promoted cellular proliferation, except for myocardial cells, and significantly increased the number of c-kit-, CXCR4- and Sca-1-positive stem cells. Moreover, the expression of SDF-1 and SCF in myocardial tissue in the EA group was significantly higher than that in the (untreated) MI group.
Conclusions:
EA appears to promote angiogenesis and reduce collagen deposition, thus improving the cardiac function of rats with MI. The underlying mechanism of action may involve endogenous stem cell mobilization mediated by SDF-1/CXCR4 and SCF/c-kit.
ABSTRACT
The lower cell survival and retention in the hostile microenvironment after transplantation has been implicated as a major bottleneck in the advancement of stem cell therapy for myocardial ...infarction (MI). In this study, we designed a novel self‐assembling peptide (SAP) by attaching prosurvival peptide QHREDGS derived from angiopoeitin‐1 to the known SAP, RADA16‐I. The mesenchymal stem cells (MSCs) were harvested from male rats and cytoprotective effect of this designer SAP (DSAP) on cultured MSCs was detected by Hoechst 33342 staining after being exposed to oxygen and glucose deprivation (OGD). The cytoprotective effect of MSCs seeded in DSAP (DSAP‐MSCs) on OGD treated cardiomyocytes was examined by TUNEL staining, phosphorylated (p‐) protein kinase B (Akt) level, and ELISA. The therapeutic potential of MSC transplantation carried in DSAP was evaluated in a female rat MI model. PBS, MSCs alone, MSCs seeded in SAP (SAP‐MSCs), or DSAP‐MSCs were transplanted into the border of the infarcted area, respectively. DSAP not only increased the proliferation of MSCs and decreased apoptosis of MSCs after OGD treatment but also promoted the secretion of IGF‐1 and HGF in MSCs. Treatment with culture supernatant of DSAP‐MSCs markedly reduced the percentage of apoptotic cardiomyocytes and increased the level of p‐Akt. Compared with the MSC group and SAP‐MSC group, DSAP‐MSC injection improved cardiac function and reduced infarct size, collagen content, and cell apoptosis. The number of Y chromosome–positive cells and microvessels in the DSAP‐MSC group was higher than those in the MSC group and SAP‐MSC group. Moreover, DSAP‐MSC transplantation down‐regulated the expression of IL‐6 and IL‐1β and up‐regulated the level of VEGF and HGF. Interestingly, miR‐21 was enriched in DSAP‐MSC‐derived exosomes (DSAP‐MSC‐Exos) and the protection against cardiomyocyte apoptosis by DSAP‐MSC‐Exos was inhibited when miR‐21 was knocked down. Furthermore, miR‐21 contributed to the improvement of cardiac function after DSAP‐MSC‐Exo injection in a rat model of MI. Additionally, the combination of DSAP and cardiotrophin‐1 (Ctf1) pretreatment further improved the survival of MSCs and the efficiency of MSC transplantation. We proposed QHREDGS‐modified SAP as an effective cell delivery system and demonstrated that MSC transplantation in this DSAP promoted angiogenesis and paracrine, thereby reducing scar size and cell apoptosis as well as improving cardiac function probably via exosome‐mediated miR‐21 after MI. Furthermore, for the first time, we proposed that DSAP, especially working together with Ctf1 pretreatment, could be a valuable way to improve the survival of MSCs and the efficiency of MSC transplantation after MI.—Cai, H., Wu, F.‐Y., Wang, Q.‐L., Xu, P., Mou, F.‐F., Shao, S.‐J., Luo, Z.‐R., Zhu, J., Xuan, S.‐S., Lu, R., Guo, H.‐D. Self‐assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction. FASEB J. 33, 8306–8320 (2019). www.fasebj.org
Stem cell-based therapeutic strategies have obtained a significant breakthrough in the treatment of cardiovascular diseases, particularly in myocardial infarction (MI). Nevertheless, limited ...retention and poor migration of stem cells are still problems for stem cell therapeutic development. Hence, there is an urgent need to develop new strategies that can mobilize stem cells to infarcted myocardial tissues effectively. Electroacupuncture (EA) intervention can improve cardiac function and alleviate myocardial injury after MI, but its molecular mechanism is still unclear. This study is aimed at observing the effects of EA treatment on the stem cell mobilization and revealing possible mechanisms in the MI model of mice. EA treatment at Neiguan (PC6) and Xinshu (BL15) acupoints was conducted on the second day after the ligation surgery. Then, the number of stem cells in peripheral blood after EA in MI mice and their cardiac function, infarct size, and collagen deposition was observed. We found that the number of CD34-, CD117-, Sca-1-, and CD90-positive cells increased at 6 h and declined at 24 h after EA intervention in the blood of MI mice. The expression of CXC chemokine receptor-4 (CXCR4) protein was upregulated at 6 h after EA treatment, while the ratio of LC3B II/I or p-ERK/ERK showed a reverse trend. In addition, there was obvious difference in EF and FS between wild-type mice and CXCR4+/− mice. The infarct size, collagen deposition, and apoptosis of the injured myocardium in CXCR4+/− mice increased but could be ameliorated by EA. In a word, our study demonstrates that EA alleviates myocardial injury via stem cell mobilization which may be regulated by the SDF-1/CXCR4 axis.
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