Publications by authors named "Shaonan Yang"

21 Publications

  • Page 1 of 1

Fucoidan Inhibits NLRP3 Inflammasome Activation by Enhancing p62/SQSTM1-Dependent Selective Autophagy to Alleviate Atherosclerosis.

Oxid Med Cell Longev 2020 6;2020:3186306. Epub 2020 Aug 6.

Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Shandong 266100, China.

NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation contributes to the progression of atherosclerosis, and autophagy inhibits inflammasome activation by targeting macrophages. We investigated whether fucoidan, a marine sulfated polysaccharide derived from brown seaweeds, could reduce NLRP3 inflammasome activation by enhancing sequestosome 1 (p62/SQSTM1)-dependent selective autophagy to alleviate atherosclerosis in high-fat-fed ApoE-/- mice with partial carotid ligation and differentiated THP-1 cells incubated with oxidized low-density lipoprotein (oxLDL). Fucoidan significantly ameliorated lipid accumulation, attenuated progression of carotid atherosclerotic plaques, deregulated the expression of NLRP3 inflammasome, autophagy receptor p62, and upregulated microtubule-associated protein light chain 3 (LC3)-II/I levels. Transmission electron microscopy and GFP-RFP-LC3 lentivirus transfection further demonstrated that fucoidan could activate autophagy. Mechanistically, fucoidan remarkably inhibited NLRP3 inflammasome activation, which was mostly dependent on autophagy. The inhibitory effects of fucoidan on NLRP3 inflammasome were enhanced by autophagy activator rapamycin (Rapa) and alleviated by autophagy inhibitor 3-methyladenine (3-MA). Fucoidan promoted the colocalization of NLRP3 and p62. Knockdown of p62 and ATG5 by small interfering RNA significantly reduced the inhibitory effects of fucoidan treatment on NLRP3 inflammasome. The data suggest that fucoidan can inhibit NLRP3 inflammasome activation by enhancing p62/SQSTM1-dependent selective autophagy to alleviate atherosclerosis.
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http://dx.doi.org/10.1155/2020/3186306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812546PMC
May 2021

Mesenchymal stem-cell-derived exosomal miR-145 inhibits atherosclerosis by targeting JAM-A.

Mol Ther Nucleic Acids 2021 Mar 4;23:119-131. Epub 2020 Nov 4.

Department of Neurology, The Affiliated Hospital of Qingdao University, Shandong 266100, China.

Atherosclerosis is a chronic inflammatory disease associated with the development of plaques that can be converted into an acute clinical event by thrombosis or plaque rupture. Mesenchymal stem cells (MSCs) exhibit therapeutic effects for the treatment of various diseases, including atherosclerosis. In this study, we show that microRNA-145 (miR-145) is associated with atherosclerosis by microRNA sequencing and bioinformatics analysis. MSC-derived miR-145-rich exosomes could efficiently deliver miR-145 from MSCs to human umbilical vein endothelial cells (HUVECs). Treatment of miR-145-rich exosomes could downregulate JAM-A, inhibit migration , and reduce atherosclerotic plaque . Our study suggests that MSC-derived miR-145-rich exosomes have great potential for atherosclerosis prevention.
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http://dx.doi.org/10.1016/j.omtn.2020.10.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732974PMC
March 2021

K63 ubiquitin chains target NLRP3 inflammasome for autophagic degradation in ox-LDL-stimulated THP-1 macrophages.

Aging (Albany NY) 2020 01 29;12(2):1747-1759. Epub 2020 Jan 29.

Department of Neurology, the Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong, China.

Inflammation, especially involving the NLRP3 inflammasome, is critical to atherosclerotic plaque formation. Enhanced autophagy can inhibit the development of atherosclerosis, and recent studies have revealed that NLRP3 inflammasome can be degraded by autophagy in atherosclerosis. In the present study, we established a foam-cell model to investigate the impact of oxidized low density lipoproteins (ox-LDLs) on autophagy and the inflammasome in atherosclerosis-related inflammation. We observed that ox-LDLs activated NLRP3 inflammasomes in macrophages and restricted autophagy in a time-and dose-dependent manner. We further observed through immunoprecipitation and siRNA knockdown that autophagic degradation of the NLRP3 inflammasome is dependent on K63 polyubiquitation of its NLRP3 subunit and subsequent binding by the adaptor protein p62. Our findings uncover a mechanism by which autophagy inhibits inflammation in atherosclerosis and the role of K63 in that process.
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http://dx.doi.org/10.18632/aging.102710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053591PMC
January 2020

MicroRNA-155 promotes the ox-LDL-induced activation of NLRP3 inflammasomes via the ERK1/2 pathway in THP-1 macrophages and aggravates atherosclerosis in ApoE-/- mice.

Ann Palliat Med 2019 Nov;8(5):676-689

Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266100, China.

Background: Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation can induce the secretion of IL-1β and IL-18 and after promoting the development of atherosclerosis. MiR-155 is an important microRNA that modulates inflammation in atherosclerosis, but the role of miR-155 in the regulation of the NLRP3 inflammasome is still unknown.

Methods: The atherosclerosis model was set up using ApoE-/- mice, and the lentiviral vector (LV) was used to interfere the expression of miR-155. HE stains was used for plaque morphology, immunohistochemistry (IHC) and western blot were used for protein expression quantification. We used oxidized low-density lipoprotein (ox-LDL) to incubate PMA-preprocessed THP-1 macrophages and detected NLRP3 inflammasome activation and ERK1/2 phosphorylation by western blot and Enzyme-linked immunosorbent assay.

Results: HE stains showed that the intravascular plaques in the miR-155-up group were remarkably increased, compared with negative control (NC) group. Results of IHC showed that the expression of caspase-1 and IL-1β in the miR-155-up group was the highest of four groups, consist with the Western blot analysis. The results of in vitro experiment show that ox-LDL promoted NLRP3 inflammasome activation and ERK1/2 phosphorylation. Blocking the ERK1/2 pathway could inhibit ox-LDL-induced NLRP3 inflammasome activation. Moreover, we found that the overexpression of miR-155 promoted the activation of the ox-LDL-induced NLRP3 inflammasome, which could also be blocked by the ERK inhibitor U0126.

Conclusions: MiR-155 aggravates the carotid AS lesion in ApoE-/- mice and exerts a regulatory effect on NLRP3 inflammasome activation in ox-LDL-induced macrophages via the ERK1/2 pathway.
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http://dx.doi.org/10.21037/apm.2019.10.11DOI Listing
November 2019

MicroRNA-181a regulates the activation of the NLRP3 inflammatory pathway by targeting MEK1 in THP-1 macrophages stimulated by ox-LDL.

J Cell Biochem 2019 08 2;120(8):13640-13650. Epub 2019 Apr 2.

Department of Neurology, The Affiliated Hospital of the Qingdao University, Medical School of Qingdao University, Qingdao, Shandong, China.

Atherosclerosis (AS) is a chronic inflammatory disease that is characterized by the deposition of lipids in the vascular wall and the formation of foam cells. Macrophages play a critical role in the development of this chronic inflammation. An increasing amount of research shows that microRNAs affect many steps of inflammation. The goal of our study was to investigate the regulatory effect of miR-181a on the NLRP3 inflammasome pathway and explore its possible mechanism. Compared with the control group, the expression of miR-181a was downregulated in the carotid tissue of AS group mice, while the expression of MEK1 and NLRP3-related proteins was upregulated significantly. In vitro, when THP-1 macrophages were stimulated with oxidized low-density lipoprotein (ox-LDL), the expression of miR-181a was decreased, the MEK/ERK/NF-κB inflammatory pathways were activated and the expression of NLRP3 inflammasome-related proteins was upregulated. Exogenous overexpression of miR-181a downregulated the activation of the MEK/ERK/NF-κB pathway and decreased the expression of NLRP3 inflammasome-related proteins (such as NLRP3, caspase-1, interleukin-18 [IL-18], IL-1β, etc). Exogenous miR-181a knockdown showed the opposite results to those of overexpression group. A luciferase reporter assay proved that miR-181a inhibited the expression of MEK1 by binding to its 3'-untranslated region. When we knocked down miR-181a and then treated cells with U0126 before ox-LDL stimulation, we found that U0126 reversed the increased activation of the MEK/ERK/NF-κB pathway and upregulation of NLRP3 inflammasome-related proteins (NLRP3, caspase-1, IL-18, IL-1β) that resulted from miR-181a knockdown. Our study suggests that miR-181a regulates the activation of the NLRP3 inflammatory pathway by altering the activity of the MEK/ERK/NF-κB pathway via targeting of MEK1.
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http://dx.doi.org/10.1002/jcb.28637DOI Listing
August 2019

LPS induces CXCL16 expression in HUVECs through the miR-146a-mediated TLR4 pathway.

Int Immunopharmacol 2019 Apr 30;69:143-149. Epub 2019 Jan 30.

Department of Neurology, The Affiliated Hospital of the Qingdao University, Medical School of Qingdao University, Qingdao, Shandong Province 266100, China. Electronic address:

Endothelial inflammation characterizes the early stages of atherosclerosis. CXCL16 is a protein that functions as both a chemokine and adhesion molecule, playing a crucial role in the pathogenesis of atherosclerosis. However, it is uncertain if LPS, a major inducer of inflammation, affects CXCL16 expression in endothelial cells and whether miR-146a, a negative regulator of atherosclerosis, participates in this process. The present study showed that exposure of human umbilical vein endothelial cells (HUVECs) to LPS induced the overexpression of CXCL16, TLR4 and NF-κB, and this induction was blocked by the TLR4 inhibitor TAK-242. In addition, LPS induced the upregulation of miR-146a in HUVECs. Overexpression or inhibition of miR-146a either inhibited or increased the LPS-induced expression CXCL16, TLR4 and NF-κB protein production, respectively. Additionally, miR-146a-induced CXCL16 expression was blocked by TAK-242. Thus, in this study, we demonstrate that LPS stimulates CXCL16 expression via the TLR4/NF-κB signaling pathway, and simultaneously, miR-146 negatively regulates LPS-induced CXCL16 expression through a TLR4-dependent mechanism.
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http://dx.doi.org/10.1016/j.intimp.2019.01.011DOI Listing
April 2019

LncRNA MALAT1 promotes oxidized low-density lipoprotein-induced autophagy in HUVECs by inhibiting the PI3K/AKT pathway.

J Cell Biochem 2019 03 28;120(3):4092-4101. Epub 2018 Nov 28.

Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.

Emerging evidence suggests that long noncoding RNAs (lncRNAs) are involved in many biological processes, such as cell growth, differentiation, apoptosis, and autophagy. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), highly expressed in endothelial cells, is well conserved and implicated in endothelial cell migration and proliferation. However, whether MALAT1 participates in oxidized low-density lipoprotein (ox-LDL)-induced autophagy regulation in human umbilical vein endothelial cells (HUVECs) remains unknown. In this study, we observed that autophagy was upregulated and MALAT1 expression was markedly increased in HUVECs treated with ox-LDL. The ox-LDL-induced autophagy of HUVECs is significantly associated with the PI3K/AKT pathway. Furthermore, we found that MALAT1 overexpression inhibited PI3K, Akt and p70S6K phosphorylation and downregulated RHEB expression, simultaneously increasing ox-LDL-induced autophagy. MALAT1 silencing caused higher phosphorylated PI3K, Akt and p70S6K levels, upregulated RHEB expression and markedly suppressed autophagy. These results indicated that lncRNA MALAT1 promotes ox-LDL-induced autophagy in HUVECs partly through the PI3K/AKT signaling pathway.
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http://dx.doi.org/10.1002/jcb.27694DOI Listing
March 2019

Associations of miR-146a, miR-149, miR-196a2, and miR-499 Polymorphisms with Ischemic Stroke in the Northern Chinese Han Population.

Med Sci Monit 2018 Oct 15;24:7366-7374. Epub 2018 Oct 15.

Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland).

BACKGROUND Recently, miR-146a C>G, miR- 149 T>C, miR-196a2 T>C and miR-499 A>G polymorphisms have been associated with susceptibility to many diseases, including ischemic stroke (IS). However, results have been reported inconsistency in IS, especially in the Chinese population. This study aimed to investigate the polymorphisms of the 4 miRNAs and IS risk in the Chinese population. MATERIAL AND METHODS We used a case-control study to explore these associations in 396 patients with IS and 378 healthy controls. According to TOAST standards, the selected patients were divided into subgroups: the large artery atherosclerosis (LAA) subgroup and the small artery occlusion (SAO) subgroup. The method of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect the genotypes. RESULTS The miR-146a C>G polymorphism was remarkably different (CC vs. CG+GG: P=0.027; CC+CG vs. GG: P=0.020; C vs. G: P=0.006). The miR-149 T>C polymorphism was also remarkably different (TT vs. TC+CC: P=0.017; TT+TC vs. CC: P=0.020; T vs. C: P=0.004). The miR-146a and miR-149 polymorphisms were also remarkably different in the LAA subgroup (P<0.05). However, we did not find an association of miR-196a2 T>C or miR-499 A>G polymorphisms with IS (P>0.05); we did not find any association in the LAA subgroup or the SAO subgroup (P>0.05). CONCLUSIONS Our study suggested that miR-146a C>G and miR-149 T>C polymorphisms might remarkably increase the risk of IS, which might be mainly associated with an increased risk in LAA stroke; however, the miR-196a2 T>C and miR-499 A>G polymorphisms might not be associated with IS risk in the northern Chinese Han population.
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http://dx.doi.org/10.12659/MSM.909935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198714PMC
October 2018

MicroRNA‑155 promotes ox‑LDL‑induced autophagy in human umbilical vein endothelial cells by targeting the PI3K/Akt/mTOR pathway.

Mol Med Rep 2018 Sep 29;18(3):2798-2806. Epub 2018 Jun 29.

Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China.

Endothelial cell autophagy has a protective role in inhibiting inflammation and preventing the development of atherosclerosis, which may be regulated by microRNA (miR)‑155. The present study aimed to investigate the mechanisms of autophagy in the development of atherosclerosis. Human umbilical vein endothelial cells model in vitro and using oxidized low‑density lipoprotein (ox‑LDL) stimulated cells to simulate the atherosclerosis. MiR‑155 mimics, miR‑155 inhibitors, and a negative control were respectively transfected in human umbilical vein endothelial cells to analyzed alterations in the expression of miR‑155. It was demonstrated that overexpression of miR‑155 promoted autophagic activity in oxidized low‑density lipoprotein‑stimulated human umbilical vein endothelial cells, whereas inhibition of the expression of miR‑155 reduced autophagic activity. Overexpression of miR‑155 revealed that it regulated autophagy via the phosphatidylinositol‑3 kinase (PI3K)/RAC‑α serine/threonine‑protein kinase (Akt)/mechanistic target of rapamycin pathway (mTOR) signaling pathway. A luciferase reporter assay demonstrated that miR‑155 directly bound to the PI3K catalytic subunit a and Ras homolog enriched in brain 3'‑untranslated region and inhibited its luciferase activity. Therefore, the results of the present study suggested that miR‑155 promoted autophagy in vascular endothelial cells and that this may have occurred via targeting of the PI3K/Akt/mTOR pathway. Thus, miR‑155 may be considered as a potential therapeutic target for the treatment of atherosclerosis.
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http://dx.doi.org/10.3892/mmr.2018.9236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102700PMC
September 2018

Rs4612666 Polymorphism of the NLRP3 Gene Is Associated with the Occurrence of Large Artery Atherosclerotic Ischemic Strokes and Microembolic Signals.

Biomed Res Int 2018 23;2018:6345805. Epub 2018 Apr 23.

Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, Shandong 266000, China.

Purpose: Large artery atherosclerosis (LAA) ischemic stroke (IS) is the most common IS subtype, and microemboli are clinically important for indicating an increased risk of IS. Nucleotide-binding domain-like receptor protein 3 (NLRP3) plays a crucial role in the pathogenesis of atherosclerosis. The aim of this study is to investigate the relationship between NLRP3 gene polymorphisms and susceptibility for LAA IS and microembolic signals (MES) in the Chinese Han population.

Methods: We studied 293 patients diagnosed with LAA IS and 265 controls. Transcranial Doppler (TCD) was used to monitor the MES in all of the patients. Depending on the presence or absence of MES, the patients were divided into MES-positive and MES-negative subgroups. PCR-RFLP or direct sequencing were used to analyze three NLRP3 gene polymorphisms.

Results: Seventy-six patients presented with MES and the MES-positive rate was 25.94%. Logistic regression analysis showed that the TT genotype frequency for the rs4612666 gene polymorphism was higher in study patients than in the controls (adjusted = 0.001) and higher in MES-positive patients compared to MES-negative patients (adjusted = 0.015). The T allele of rs4612666 was associated with an increased risk for developing LAA IS and MES ( = 0.001; = 0.015, resp.). Prevalence of the CCC haplotype was higher in the controls than in the patients ( = 0.009) and prevalence of the TGT haplotype was lower in the controls than in the patients ( = 0.019).

Conclusions: The NLRP3 rs4612666 gene polymorphism may be related to the occurrence of LAA IS and MES, suggesting that the NLRP3 gene polymorphism increases the susceptibility of LAA IS by changing the plaque vulnerability.
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http://dx.doi.org/10.1155/2018/6345805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937605PMC
October 2018

MiR-181b regulates autophagy in a model of Parkinson's disease by targeting the PTEN/Akt/mTOR signaling pathway.

Neurosci Lett 2018 05 30;675:83-88. Epub 2018 Mar 30.

Department of Neurology, The Affiliated Hospital of the Qingdao University, Qingdao, Shandong, 266100, China. Electronic address:

Objective: Parkinson's disease (PD) is the second most common neurodegenerative disease. Recent studies have shown that dysregulation of microRNA plays an important role in PD, and defects in autophagy are also critically associated with mechanisms underlying PD. We aim to investigate the effect of miR-181b on autophagy, particularly the involvement of miR-181b in the regulation of the phosphatase and tensin homolog (PTEN)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway and neuronal autophagy in a 1-methyl-4- phenylpyridinium iodide(MPP)-induced cellular model of Parkinson's disease.

Materials And Methods: We used MPP as a tool to construct the PD cell model, using miR-181b mimics or inhibitors to regulate the expression of miR-181b. PC12 cell viability was detected by MTT. The expression of miR-181b was determined by quantitative real-time PCR analysis. The expression of autophagy protein markers (LC3II) and PTEN/Akt/mTOR signaling proteins (PTEN, p-AKT,p-mTOR and p-p70S6K) were determined by Western blotting analysis.

Results: The expression of miR-181b and autophagy-related proteins was gradually decreased with increasing MPP content. Overexpression of miR-181b significantly decreased the LC3II/GAPDH ratio and increased cell viability compared to the MPP treated group, whereas inhibition of miR-181b attenuated these effects. In addition, we observed that PTEN expression was reduced by miR-181b mimics and induced by its inhibitors in MPP-treated PC12 cells. Additionally, the indicators of AKT/mTOR signaling, phosphorylated (active) AKT, mTOR and p70S6K were both increased by miR-181b mimics and decreased by its inhibitors.

Conclusions: Our results suggest that miR-181b regulates autophagy by targeting the PTEN/Akt/mTOR signaling pathway, thereby affecting cell viability in PD.
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http://dx.doi.org/10.1016/j.neulet.2018.03.041DOI Listing
May 2018

Biomarkers of cerebral microembolic signals.

Clin Chim Acta 2017 Dec 27;475:164-168. Epub 2017 Oct 27.

Department of Neurology, The Affiliated Hospital of Qingdao University, Medical School of Qingdao University, Qingdao, Shandong Province 266100, China. Electronic address:

Stroke is a major cause of mortality and morbidity around the world. Microembolic signals (MES), as the markers of unstable atherosclerotic plaque, can predict the occurrence and prognosis of ischemic stroke (IS). MES can also assess the efficacy of antithrombotic agents and predict the recurrence probability of IS. Unstable plaques are the main source of MES; thus, numerous biomarkers of atherosclerotic plaque instability are highly likely to predict the presence of MES. This study aims to review recent biomarker candidates for MES or microembolism. Current research indicates that the following are independent markers for positive MES: high level of serum soluble P-selectin, chemokine (C-X-C motif) ligand 16 (CXCL16) and fibrinogen, high neutrophil count, reduced ratio of CD4+CD25 regulatory T cells (Tregs) and the C allele of tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) rs3102735. However, a more integrated profile of biomarkers for MES is needed to improve the stratification of patients with carotid stenosis and enhance the effectiveness of therapeutic interventions and prevention for IS.
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http://dx.doi.org/10.1016/j.cca.2017.10.028DOI Listing
December 2017

miR-155 Promotes ox-LDL-Induced Autophagy in Human Umbilical Vein Endothelial Cells.

Mediators Inflamm 2017 4;2017:9174801. Epub 2017 Jun 4.

Central Laboratory, The Affiliated Hospital of the Qingdao University, Qingdao, Shandong 266100, China.

As an evolutionarily conserved metabolic process, autophagy is involved in the process of atherosclerosis (AS). MicroRNA-155 (miR-155), a multifunctional miRNA, plays an important role in many physiological and pathological conditions, including AS and autophagy. However, the effect of miR-155 on the regulation of autophagy in endothelial cells has not been reported to date. Therefore, the objective of our study was to investigate the role of miR-155 in autophagy induced by oxidized low-density lipoprotein (ox-LDL) in human umbilical vein endothelial cells (HUVECs). Our results demonstrated that ox-LDL induced autophagy in HUVECs and increased the expression of miR-155 significantly. Overexpression of miR-155 improved autophagic activity, whereas low expression of miR-155 inhibited autophagic activity. Therefore, the data demonstrated that miR-155 has a modulating effect on the autophagy of vascular endothelial cells.
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http://dx.doi.org/10.1155/2017/9174801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474275PMC
March 2018

Expression of miRNA-155 in carotid atherosclerotic plaques of apolipoprotein E knockout (ApoE) mice and the interventional effect of rapamycin.

Int Immunopharmacol 2017 May 6;46:70-74. Epub 2017 Mar 6.

Laboratory of Human Micromorphology, The Medical College of Qingdao University, Qingdao 266003, PR China.

Carotid atherosclerosis (AS) is an inflammatory process and is the primary pathogenesis of cerebrovascular disease. Many factors are responsible for development of atherosclerosis such as inflammation and autophagy. It is reported that microRNAs (miRNAs) could regulate the development of atherosclerosis through targeting autophagy-related genes. Many studies have demonstrated that miRNA-155 could regulate autophagy in macrophages or tumor cells. However, the role of miRNA-155 on autophagy in carotid plaques is not yet known. In this study, we explore the expression of miRNA-155 and autophagy-related proteins in carotid plaques of ApoE mice and the interventional effect of rapamycin. We compared the expression of miRNA-155 and autophagy-related proteins between the control, model and rapamycin groups using qRT-PCR and western blot. Compared to the control group, we found the miRNA-155 and LC3-II expression was up-regulated (P<0.05), expression ratio of phosphorylated mammalian target of rapamycin to total mammalian target of rapamycin (p-mTOR/mTOR) was down-regulated in model group (P<0.05), but atherosclerotic lesions were still aggravated. These results following rapamycin group indicated that miRNA-155 and LC3-II expression was significantly up-regulated (P<0.05), the expression ratio of p-mTOR/mTOR was significantly down-regulated (P<0.05), and atherosclerotic lesions were reduced. Our results showed in the early stages of atherosclerotic plaques development, effective autophagy could attenuate atherosclerosis in ApoE mice. Furthermore, our results also demonstrated that rapamycin might promote the activation of the autophagy by enhancing the expression of miRNA-155, which delays the development of atherosclerotic plaques.
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http://dx.doi.org/10.1016/j.intimp.2017.02.026DOI Listing
May 2017

Plasma levels of miR-137 and miR-124 are associated with Parkinson's disease but not with Parkinson's disease with depression.

Neurol Sci 2017 May 8;38(5):761-767. Epub 2017 Feb 8.

Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, People's Republic of China.

MicroRNAs (miRNAs) are a class of small, non-coding RNAs that regulate gene expression at the post-transcriptional level. Recently, it was reported that miR-137, miR-124, and miR-184 were widely expressed in the central nervous system and were vital to neuronal regulation. In this study, we detected the circulating levels of miR-137, miR-124, and miR-184 in PD patients, and explored the potential role of miR-124, miR-137, and miR-184 in the diagnosis of PD. We further described the relationship between these miRNAs and PD with depression (PD-Dep). The study recruited 60 controls and 60 PD patients, which were further divided into two subgroups, PD with depression (PD-Dep, n = 24) and non-depressed group (PD-NDep, n = 36) according to Hamilton Rating Scale for Depression. Plasma levels of miR-137, miR-124, and miR-184 were detected by qRT-PCR. Receiver-operating characteristic (ROC) curve was used to evaluate miR-124 and miR-137 levels as potential diagnostic biomarkers for PD. The results demonstrated that there were no significant differences in levels of miR-184 between PD patients and controls (p > 0.05). However, miR-137 levels were increased significantly for PD patients compared to controls (p < 0.05), while miR-124 levels were down-regulated (p < 0.05). The areas under the ROC curve (AUC) of miR-137 and miR-124 were 0.707 (95% CI 0.615-0.789, p < 0.05) and 0.709 (95% CI 0.618-0.633, p < 0.05), respectively. Correlation analysis revealed that there was no relationship between these two miRNAs levels and UPDRS scores or H&Y stage. There were no significant differences in miR-137 and miR-124 levels between PD-Dep and PD-NDep (p > 0.05). Thus, plasma levels of miR-137 and miR-124 are associated with Parkinson's disease and might be potential biomarkers of the diagnosis of PD. There were no associations of plasma miR-137 and miR-124 with the severity of PD motor symptoms or PD-Dep.
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http://dx.doi.org/10.1007/s10072-017-2841-9DOI Listing
May 2017

Increase of Serum CXCL16 Level Correlates Well to Microembolic Signals in Acute Stroke Patients with Carotid Artery Stenosis.

Clin Chim Acta 2016 Sep 26;460:67-71. Epub 2016 Jun 26.

Department of Neurology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, Province, 266100, PR China. Electronic address:

Background: The majority of strokes are combined with the instability of atherosclerotic plaques. Microembolic signals (MES) have been considered as evidence of plaque destabilization. We found that increased CXCL16 correlated to atherosclerotic ischemic stroke. Thus, we explored whether CXCL16 correlates to MES.

Methods: The study recruited 104 controls and 118 patients with acute ischemic stroke that has an ipsilateral carotid artery stenosis of >50%. The ipsilateral middle cerebral artery of patients was insonated for 60min using Doppler device within 72h of their clinical presentation.

Results: We found that CXCL16 was significantly increased in the stroke patients. Furthermore, there was a significant difference in CXCL16 between the MES-positive and MES-negative patients. Using CXCL16 to distinguish the controls and stroke patients, the area under the ROC curve (AUC) was 0.722; the cut-off value was 2.015ng/ml. The sensitivity and specificity were 70.5% and 67.9%, respectively. Furthermore, if we used CXCL16 to distinguish the MES-positive and MES-negative patients, the AUC was 0.736; the cut-off value was 2.115ng/ml. The sensitivity and specificity were 88.5% and 56.5%, respectively.

Conclusions: Higher levels CXCL16 may be a biomarker for predicting stroke incidence and might contribute to plaque destabilization.
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http://dx.doi.org/10.1016/j.cca.2016.06.026DOI Listing
September 2016

Atorvastatin Upregulates the Expression of miR-126 in Apolipoprotein E-knockout Mice with Carotid Atherosclerotic Plaque.

Cell Mol Neurobiol 2017 Jan 17;37(1):29-36. Epub 2016 Feb 17.

Department of Neurology, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, Shandong, People's Republic of China.

Carotid atherosclerosis (AS) is a chronic inflammatory disease of the carotid arterial wall, which is very important in terms of the occurrence of cerebral vascular accidents. Studies have demonstrated that microRNAs (miRNAs) and their target genes are involved in the formation of atherosclerosis and that atorvastatin might reduce atherosclerotic plaques by regulating the expression of miRNAs. However, the related mechanism is not yet known. In this study, we first investigated the effects of atorvastatin on miR-126 and its target gene, i.e., vascular cell adhesion molecule-1 (VCAM-1) in apolipoprotein E-knockout (ApoE-/-) mice with carotid atherosclerotic plaque in vivo. We compared the expressions of miR-126 and VCAM-1 between the control, atherosclerotic model and atorvastatin treatment groups of ApoE-/- mice using RT-PCR and Western blot. We found the miR-126 expression was significantly down-regulated, and the VCAM-1 expression was significantly up-regulated in the atherosclerotic model group, which accelerated the progression of atherosclerosis in the ApoE-/- mice. These results following atorvastatin treatment indicated that miR-126 expression was significantly up-regulated, VCAM-1 expression was significantly down-regulated and atherosclerotic lesions were reduced. The present results might explain the mechanism by which miR-126 is involved in the formation of atherosclerosis in vivo. Our study first indicated that atorvastatin might exert its anti-inflammatory effects in atherosclerosis by regulating the expressions of miR-126 and VCAM-1 in vivo.
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http://dx.doi.org/10.1007/s10571-016-0331-xDOI Listing
January 2017

Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an AβPP/PS1 transgenic mouse model.

Stem Cell Res Ther 2013 Jul 4;4(4):76. Epub 2013 Jul 4.

Introduction: Cell therapy is a potential therapeutic approach for neurodegenerative disorders, such as Alzheimer disease (AD). Neuronal differentiation of stem cells before transplantation is a promising procedure for cell therapy. However, the therapeutic impact and mechanisms of action of neuron-like cells differentiated from human umbilical cord mesenchymal stem cells in AD have not been determined.

Methods: In this study, we used tricyclodecan-9-yl-xanthogenate (D609) to induce human mesenchymal stem cells isolated from Wharton jelly of the umbilical cord (HUMSCs) to differentiate into neuron-like cells (HUMSC-NCs), and transplanted the HUMSC-NCs into an AβPP/PS1 transgenic AD mouse model. The effects of HUMSC-NC transplantation on the cognitive function, synapsin I level, amyloid β-peptides (Aβ) deposition, and microglial function of the mice were investigated.

Results: We found that transplantation of HUMSC-NCs into AβPP/PS1 mice improved the cognitive function, increased synapsin I level, and significantly reduced Aβ deposition in the mice. The beneficial effects were associated with "alternatively activated" microglia (M2-like microglia). In the mice transplanted with HUMSC-NCs, M2-like microglial activation was significantly increased, and the expression of antiinflammatory cytokine associated with M2-like microglia, interleukin-4 (IL-4), was also increased, whereas the expression of proinflammatory cytokines associated with classic microglia (M1-like microglia), including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), was significantly reduced. Moreover, the expression of Aβ-degrading factors, insulin-degrading enzyme (IDE) and neprilysin (NEP), was increased substantially in the mice treated with HUMSC-NCs.

Conclusions: HUMSC-NC transplantation decreased Aβ deposition and improved memory in AβPP/PS1 mice by a mechanism associated with activating M2-like microglia and modulating neuroinflammation. Transplantation of neuron-like cells differentiated from mesenchymal stem cells might be a promising cell therapy for Alzheimer disease.
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http://dx.doi.org/10.1186/scrt227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854736PMC
July 2013

Cholinergic neuron-like cells derived from bone marrow stromal cells induced by tricyclodecane-9-yl-xanthogenate promote functional recovery and neural protection after spinal cord injury.

Cell Transplant 2013 1;22(6):961-75. Epub 2012 Oct 1.

Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, China.

The rate of neuronal differentiation of bone marrow stromal cells (BMSCs) in vivo is very low; therefore, it is necessary to elevate the number of BMSC-derived neurons to cure neurodegenerative diseases. We previously reported that tricyclodecane-9-yl-xanthogenate (D609), an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), induced BMSCs to differentiate into neuron-like cells in vitro. However, the neuronal type is not clear, and it is still unknown whether these neuron-like cells possess physiological properties of functional neurons and whether they can contribute to the recovery of neuron dysfunction. To answer these questions, we investigated their characteristics by detecting neuronal function-related neurotransmitters and calcium image. The results showed that these cells exhibited functional cholinergic neurons in vitro. Transplantation of these cholinergic neuron-like cells promoted the recovery of spinal cord-injured mice, and they were more effective than BMSCs. The number of cholinergic neurons was increased after injection with BMSC-derived cholinergic neuron-like cells, indicating their high differentiation rate in vivo. Moreover, the proportion of cholinergic neurons in host cells and secretion of acetylcholine were increased, and preservation of neurofilament was also observed in the lesion of mice implanted with BMSC-derived neurons, suggesting the neuronal protection of BMSC-derived neurons. Our findings provide both a simple method to induce the differentiation of BMSCs into cholinergic neuron-like cells and a putative strategy for the therapy of spinal cord injuries.
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http://dx.doi.org/10.3727/096368912X657413DOI Listing
February 2014

A butyrolactone derivative 3BDO alleviates memory deficits and reduces amyloid-β deposition in an AβPP/PS1 transgenic mouse model.

J Alzheimers Dis 2012 ;30(3):531-43

Department of Neural Medicine, Second Hospital of Shandong University, Jinan, China.

Excessive extracellular deposition of amyloid- peptide (Aβ) in the brain is the pathological hallmark of Alzheimer's disease (AD). Cumulative evidence indicates that autophagy is involved in the metabolism of Aβ and pathogenesis of AD. However, the molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. We recently found that long-term treatment with a butyrolactone derivative 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran- 2(3 H)-one (3BDO) increased levels of insulin-degrading enzyme and neprilysin, suppressed autophagy via an mTOR pathway, lowered levels of Aβ, and prevented AD-like cognitive deficits in the AβPP/PS1 double transgenic mouse model. Therefore, our findings suggest that 3BDO may be beneficial in the prevention and treatment of AD.
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http://dx.doi.org/10.3233/JAD-2012-111985DOI Listing
October 2012

Butyrolactone derivative 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one protects against amyloid-β peptides-induced cytotoxicity in PC12 cells.

J Alzheimers Dis 2012 ;28(2):345-56

Department of Neural Medicine, Second Hospital of Shandong University, Jinan, China.

Excessive extracellular deposition of amyloid-β peptides (Aβ) is a characteristic pathologic feature of Alzheimer's disease (AD). Accumulating evidence indicates that macroautophagy is involved in the pathogenesis of AD, but the exact role of macroautophapy is still unclear. We investigated whether Aβ(25-35) could cause reactive oxygen species (ROS) accumulation, decrease the activity of Na(+), K(+)-ATPase, trigger an autophagy process, and inhibit the growth of PC12 cells and examined the effect of a new autophagy modulator, butyrolactone derivative 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3 H)-one (3BDO). 3BDO could block the decrease in cell viability induced by Aβ(25-35) by inhibiting ROS accumulation and the decrease in activity of Na(+), K(+)-ATPase and the autophagy process. In addition, 3BDO modulated the autophagy progress via a mammalian target of rampamycin-dependent pathway. 3BDO has a protective effect against the cytotoxicity induced by Aβ(25-35) and might be a promising tool for AD research.
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http://dx.doi.org/10.3233/JAD-2011-110863DOI Listing
May 2012