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
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.
Image 1
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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.
Autophagy is required for the maintenance of cardiomyocyte homeostasis. However, excessive autophagy plays a maladaptive role in pressure overload-induced heart failure. To identify mechanisms by ...which Stachydrine inhibits pressure overload-induced cardiac hypertrophy, we determined inhibitory activities against activation of NADPH oxidase, reactive oxygen species(ROS) production and excessive activation of autophagy.
Stachydrine was administered intragastrically to Wistar rats after Transverse aortic constriction(TAC) and H9c2 cells were treated with Stachydrine after Angiotension II stimulation. The activation of NADPH oxidase2 required the membrane translocation of p47phox and p67phox. Cell membrane fraction was isolated by ultracentrifuge in sucrose. The expression of p67phox, p47phox, gp91phox subunit in the cell membrane were determined by western blot. The combination of p67phox and gp91 phox subunit was detected by immunofluorescence staining. The expression of phosphorylated p47phox subunit was determined by western blot. The intracellular ROS were measured with DCF-DA fluoresence. The autophagic flux was measured by recording the fluorescence emission of the fusion protein mRFP-GFP-LC3 by dynamic live-cell imaging. Reuslts: We report here that stachydrine, a major constituent of Leonurus heterophyllus Sweet, inhibited AngII-induced excessive autophagy within H9c2 cells. Stachydrine blocked the over phosphorylation of the p47phox subunit, decreased the translocation of p47phox and p67phox to the membrane, inhibited the activity of NOX2, and reduced the generation of ROS. We also demonstrated that stachydrine ameliorated TAC-induced cardiac hypertrophy, dysfunction and excessive autophagy in vivo.
Our study highlights the importance of regulating NOX2 when autophagy is obviously activated. By inhibiting NOX2, Stachydrine inhibits ROS production, thus exerting a remarkable activity of inhibiting hypertrophy, which could have considerable effect on clinical practice.
20(S)‐protopanaxadiol (PPD)‐type ginsenosides are generally believed to be the most pharmacologically active components of Panax ginseng. These compounds induce apoptotic cell death in various cancer ...cells, which suggests that they have anti‐cancer activity. Anti‐angiogenesis is a promising therapeutic approach for controlling angiogenesis‐related diseases such as malignant tumors, age‐related macular degeneration, and atherosclerosis. Studies showed that 20(S)‐PPD at low concentrations induces endothelial cell growth, but in our present study, we found 20(S)‐PPD at high concentrations inhibited cell growth and mediated apoptosis in human umbilical vein endothelial cells (HUVECs). The mechanism by which high concentrations of 20(S)‐PPD mediate endothelial cell apoptosis remains elusive. The present current study investigated how 20(S)‐PPD induces apoptosis in HUVECs for the first time. We found that caspase‐9 and its downstream caspase, caspase‐3, were cleaved into their active forms after 20(S)‐PPD treatment. Treatment with 20(S)‐PPD decreased the level of Bcl‐2 expression but did not change the level of Bax expression. 20(S)‐PPD induced endoplasmic reticulum stress in HUVECs and stimulated UPR signaling, initiated by protein kinase R‐like endoplasmic reticulum kinase (PERK) activation. Total protein expression and ATF4 nuclear import were increased, and CEBP‐homologous protein (CHOP) expression increased after treatment with 20(S)‐PPD. Furthermore, siRNA‐mediated knockdown of PERK or ATF4 inhibited the induction of CHOP expression and 20(s)‐PPD‐induced apoptosis. Collectively, our findings show that 20(S)‐PPD inhibits HUVEC growth by inducing apoptosis and that ATF4 expression activated by the PERK‐eIF2α signaling pathway is essential for this process. These findings suggest that high concentrations of 20(S)‐PPD could be used to treat angiogenesis‐related diseases.
In this study, we show that 20(S)‐PPD inhibits HUVEC growth by inducing apoptosis and that ATF4 expression activated by the PERK‐eIF2α signaling pathway is essential for this process.
With the upsurge of artificial intelligence (AI) technology in the medical field, its application in ophthalmology has become a cutting-edge research field. Notably, machine learning techniques have ...shown remarkable achievements in diagnosing, intervening, and predicting ophthalmic diseases. To meet the requirements of clinical research and fit the actual progress of clinical diagnosis and treatment of ophthalmic AI, the Ophthalmic Imaging and Intelligent Medicine Branch and the Intelligent Medicine Committee of Chinese Medicine Education Association organized experts to integrate recent evaluation reports of clinical AI research at home and abroad and formed a guideline on clinical research evaluation of AI in ophthalmology after several rounds of discussion and modification. The main content includes the background and method of developing this guideline, an introduction to international guidelines on the clinical research evaluation of AI, and the evaluation methods of clinical ophthalmic AI models. This guideline introduces general evaluation methods of clinical ophthalmic AI research, evaluation methods of clinical ophthalmic AI models, and commonly-used indices and formulae for clinical ophthalmic AI model evaluation in detail, and amply elaborates the evaluation methods of clinical ophthalmic AI trials. This guideline aims to provide guidance and norms for clinical researchers of ophthalmic AI, promote the development of regularization and standardization, and further improve the overall level of clinical ophthalmic AI research evaluations.
Compound Dihuang Granule (CDG) is widely used in traditional Chinese medicine (TCM) for the treatment of Parkinson's disease (PD). It has been shown to alleviate PD symptoms. However, the molecular ...mechanisms of its action have not been established. To establish the molecular mechanisms of CDG against PD, we used TCM network pharmacology methods to predict its molecular targets and signaling pathways, followed by experimental validation. The Core Protein protein interaction (PPI) network of the 150 intersections between CDG and PD-related genes, comprising 23 proteins, including CASP3 (caspase-3), MAPK8 (JNK), FOS (c-Fos), and JUN (c-Jun). KEGG and GO analyses revealed that apoptotic regulation and MAPK signaling pathways were significantly enriched. Since c-Jun and c-Fos are AP-1 subunits, an important downstream JNK effector, we investigated if the JNK/AP-1 pathway influences CDG against apoptosis through the nigrostriatal pathways in PD rat models. Molecular docking analysis found that the top three bioactive compounds exhibiting the highest Degree Centrality following online database and LC-MS analysis had high affinities for JNK. Experimental validation analysis showed that CDG decreased the number of rotating laps and suppressed the levels of phosphorylated c-Jun, c-Fos, and JNK, as well as the number of TUNEL positive cells and the cleaved caspase-3 level in the nigrostriatal pathway. Furthermore, CDG treatment elevated the number of TH neurons, TH expression level, and Bcl-2/Bax protein ratio in a 6-OHDA-induced PD rat. These findings are in tandem with those obtained using SP600125, a specific JNK inhibitor. In conclusion, CDG suppresses the apoptosis of the nigrostriatal pathway and relieves PD symptoms by suppressing the JNK/AP-1 signaling pathway.
To gain insights into the global research hotspots and trends of myopia.
Articles were downloaded from January 1, 2013 to December 31, 2022 from the Science Core Database website and were mainly ...statistically analyzed by bibliometrics software.
A total of 444 institutions in 87 countries published 4124 articles. Between 2013 and 2022, China had the highest number of publications (
=1865) and the highest H-index (61). Sun Yat-sen University had the highest number of publications (
=229) and the highest H-index (33). Ophthalmology is the main category in related journals. Citations from 2020 to 2022 highlight keywords of options and reference, child health (pediatrics), myopic traction mechanism, public health, and machine learning, which represent research frontiers.
Myopia has become a hot research field. China and Chinese institutions have the strongest academic influence in the field from 2013 to 2022. The main driver of myopic research is still medical or ophthalmologists. This study highlights the importance of public health in addressing the global rise in myopia, especially its impact on children's health. At present, a unified theoretical system is still needed. Accurate surgical and therapeutic solutions must be proposed for people with different characteristics to manage and intervene refractive errors. In addition, the benefits of artificial intelligence (AI) models are also reflected in disease monitoring and prediction.
Purpose - An appropriate fixture layout can decrease the assembly variation of Aeronautical Thin-Walled Structure (ATWS) substantially. The purpose of this paper is to develop a fixture layout method ...to minimize variation.Design methodology approach - The paper uses genetic algorithm and ants algorithm (GAAA) to optimize the fixture layout by first, analyzing the "N-2-1" positioning principle of ATWS riveting, and then developing a hierarchical fixture layout model to represent the base points and locating points of ATWS. Second, information of base points and locating points is coded as gene and chromosome, according to a special coding rule and the fixture layout model. The fitness is also defined by the assembly variation of key characteristic points (KCPs). Third, the genetic and ants manipulations are discussed individually, and the two parts are connected by threshold value of the probability for chromosome in the genetic manipulation.Findings - The method can solve the fixture layout problem of ATWS with automated riveting efficiently, which is shown as an example in this paper.Practical implications - The assembly variation is decreased by using the method presented in this paper according to the variation comparison.Originality value - The hierarchical fixture layout model is proposed for the first time in this paper and base points and locating points are optimized successfully by the GAAA.
BackgroundAcupuncture is a potential therapy for Alzheimer's disease (AD), but its clinical effects and underlying mechanisms are not fully understood. Emerging evidence suggests autophagy is ...involved in β-amyloid (Aβ) clearance. We hypothesised that electroacupuncture (EA) treatment of AD involves the autophagy pathway in rats.MethodsWe injected 2μl Aβ1–40 bilaterally into the hippocampi of 42 rats to establish AD. Rats remained untreated (AD group, n=14) or received 24 EA treatments at GV20+BL23 over 28 days from day 7 post-injection with/without co-treatment with 3-methyladenine (3-MA), an autophagy inhibitor (AD+EA+3-MA and AD+EA groups, respectively, n=14 each). Cognitive function was evaluated by Morris water maze (MWM) testing. Hippocampi were examined by transmission electron microscopy (TEM) and stained with haematoxylin and eosin/transferase dUTP nick end labelling (TUNEL) to assess neuronal morphology/apoptosis, respectively. Protein expression of Beclin-1, LC3 and Aβ1-40 was examined.ResultsIn the MWM test, the AD+EA group showed an improvement in parameters consistent with improved learning/memory compared to untreated AD rats, and 3-MA attenuated these effects. EA mitigated cellular apoptosis resulting from Aβ infusion in the CA1 region and enhanced LC3II/LC3I ratios and Beclin-1 expression. Numerous autophagosome precursors and enlarged autophagosomes were observed by TEM in the hippocampi of EA-treated rats. Reduced Aβ levels, and co-localisation of Aβ and LC3II, were observed following EA treatment by immunofluorescence staining. EA+3-MA treated rats had much higher TUNEL-positive neurons, lower LC3II/LC3I ratios and Beclin-1 expression, and elevated Aβ levels compared with EA alone.ConclusionsEA reduces neuronal apoptosis, enhances degradation of Aβ, and improves learning/memory in AD rats by upregulating the autophagy pathway.
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