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Yuan, Ximing
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Publications (10 of 58) Show all publications
Liang, W., Ward, L., Karlsson, H., Ljunggren, S., Li, W., Lindahl, M. & Yuan, X. (2016). Distinctive proteomic profiles among different regions of human carotid plaques in men and women. Scientific Reports, 6(26231)
Open this publication in new window or tab >>Distinctive proteomic profiles among different regions of human carotid plaques in men and women
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 26231Article in journal (Refereed) Published
Abstract [en]

The heterogeneity of atherosclerotic tissue has limited comprehension in proteomic and metabolomic analyses. To elucidate the functional implications, and differences between genders, of atherosclerotic lesion formation we investigated protein profiles from different regions of human carotid atherosclerotic arteries; internal control, fatty streak, plaque shoulder, plaque centre, and fibrous cap. Proteomic analysis was performed using 2-DE with MALDI-TOF, with validation using nLC-MS/MS. Protein mapping of 2-DE identified 52 unique proteins, including 15 previously unmapped proteins, of which 41 proteins were confirmed by nLC-MS/MS analysis. Expression levels of 18 proteins were significantly altered in plaque regions compared to the internal control region. Nine proteins showed site-specific alterations, irrespective of gender, with clear associations to extracellular matrix remodelling. Five proteins display gender-specific alterations with 2-DE, with two alterations validated by nLC-MS/MS. Gender differences in ferritin light chain and transthyretin were validated using both techniques. Validation of immunohistochemistry confirmed significantly higher levels of ferritin in plaques from male patients. Proteomic analysis of different plaque regions has reduced the effects of plaque heterogeneity, and significant differences in protein expression are determined in specific regions and between genders. These proteomes have functional implications in plaque progression and are of importance in understanding gender differences in atherosclerosis.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-129495 (URN)10.1038/srep26231 (DOI)000376554600001 ()27198765 (PubMedID)
Note

Funding Agencies|Swedish Heart Lung Foundation; Linkoping University Hospital Research foundation; Swedish Institute; China Scholarship Council

Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2018-03-27
Johansson, M. E., Zhang, X.-Y., Edfeldt, K., Lundberg, A. M., Levin, M. C., Boren, J., . . . Yan, Z.-Q. (2014). Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid-rich necrotic cores in hypercholesterolemic mice. European Journal of Immunology, 44(10), 3081-3092
Open this publication in new window or tab >>Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid-rich necrotic cores in hypercholesterolemic mice
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2014 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 44, no 10, p. 3081-3092Article in journal (Refereed) Published
Abstract [en]

Atherosclerosis is an inflammatory disease associated with the activation of innate immune TLRs and nucleotide-binding oligomerization domain-containing protein (NOD)like receptor pathways. However, the function of most innate immune receptors in atherosclerosis remains unclear. Here, we show that NOD2 is a crucial innate immune receptor influencing vascular inflammation and atherosclerosis severity. 10-week stimulation with muramyl dipeptide (MDP), the NOD2 cognate ligand, aggravated atherosclerosis, as indicated by the augmented lesion burden, increased vascular inflammation and enlarged lipid-rich necrotic cores in Ldlr(-/-) mice. Myeloid-specific ablation of NOD2, but not its downstream kinase, receptor-interacting serine/threonine-protein kinase 2, restrained the expansion of the lipid-rich necrotic core in Ldlr(-/-) chimeric mice. In vitro stimulation of macrophages with MDP enhanced the uptake of oxidized low-density lipoprotein and impaired cholesterol efflux in concordance with upregulation of scavenger receptor A1/2 and downregulation of ATP-binding cassette transporter A1. Ex vivo stimulation of human carotid plaques with MDP led to increased activation of inflammatory signaling pathways p38 MAPK and NF-kappa B-mediated release of proinflammatory cytokines. Altogether, this study suggests that NOD2 contributes to the expansion of the lipid-rich necrotic core and promotes vascular inflammation in atherosclerosis.

Place, publisher, year, edition, pages
Wiley-VCH Verlag, 2014
Keywords
Atherosclerosis; Inflammation; Innate immunity; Nucleotide-binding oligomerization domain-containing protein 2; Pattern recognition receptor
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-112483 (URN)10.1002/eji.201444755 (DOI)000343827600024 ()25042478 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Heart-Lung Foundation; European Union projects (Immunath, AtheroRemo, AtheroFlux); O. E. och Edla Johanssons vetenskapliga stiftelse; KI foundation; KI Joint funding postdoc position; Swedish Society for Medical Research; Chinese Scholarship Council; Peking University Health Science Center; National Health and Medical Research Council of Australia

Available from: 2014-11-28 Created: 2014-11-28 Last updated: 2017-12-05
Miah, S., Zadeh, S. N., Yuan, X.-M. & Li, W. (2013). Expression of Egr1 and p53 in human carotid plaques and apoptosis induced by 7-oxysterol or p53.. Experimental and Toxicological Pathology, 65(5), 677-682
Open this publication in new window or tab >>Expression of Egr1 and p53 in human carotid plaques and apoptosis induced by 7-oxysterol or p53.
2013 (English)In: Experimental and Toxicological Pathology, ISSN 0940-2993, E-ISSN 1618-1433, Vol. 65, no 5, p. 677-682Article in journal (Refereed) Published
Abstract [en]

Egr-1 and p53 are involved in pathology of both atherosclerosis and cancer. However, it is unknown whether p53 and Egr1 are interactively involved in apoptosis in atherosclerosis. We found that in human carotid plaques, the expression of p53 was inversely correlated with Egr1. In U937 cells, 7 beta-hydroxycholesterol and 7-ketocholesterol induced production of reactive oxygen species (ROS), transient up-regulation of Egr1 followed by late induction of p53 and apoptosis. Cells with nuclear fragmentation induced by 7-oxysterol or p53 showed increased levels of p53, but decreased levels of Egr1. In conclusion, ROS induced by 7-oxysterols may function as an early initiator of Egr1 expression. The late induced p53 by 7-oxysterols contributes to apoptotic cell death and is linked to the reduction of Egr1 levels, which resembles the differential expression of p53 and Egr1 in human atheroma progression.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90234 (URN)10.1016/j.etp.2012.08.002 (DOI)000322292700028 ()22999639 (PubMedID)
Available from: 2013-03-21 Created: 2013-03-21 Last updated: 2017-12-06
Laskar, A., Eilertsen, J., Li, W. & Yuan, X.-M. (2013). SPION primes THP1 derived M2 macrophages towards M1-like macrophages. Biochemical and Biophysical Research Communications - BBRC, 441(4), 737-742
Open this publication in new window or tab >>SPION primes THP1 derived M2 macrophages towards M1-like macrophages
2013 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 441, no 4, p. 737-742Article in journal (Refereed) Published
Abstract [en]

Potentially, cellular iron regulates functional plasticity in macrophages yet; interaction of functionally polarized macrophages with iron-oxide nanoparticles has never been studied. We found that monocyte differentiation alters cellular ferritin and cathepsin L levels and induces functional polarization in macrophages. Iron in super paramagnetic iron-oxide nanoparticle (SPION) induces a phenotypic shift in THP1 derived M2 macrophages towards a high CD86+ macrophage subtype. This phenotypic shift was accompanied by up-regulated intracellular levels of ferritin and cathepsin L in M2 macrophages, which we found as a characteristic hallmark of M1 macrophages. Atherogenic oxysterols reduce phagocytic activity in both macrophage subtypes and thus these cells may escape detection by ironoxide nanoparticles (INPs) in-vivo.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Cathepsin L; Ferritin; Iron-oxide nanoparticles; M1 and M2 macrophages; Oxysterols
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-91999 (URN)10.1016/j.bbrc.2013.10.115 (DOI)000328434800008 ()
Available from: 2013-05-07 Created: 2013-05-07 Last updated: 2017-12-06Bibliographically approved
Li, W., Laskar, A., Sultana, N., Osman, E., Ghosh, M., Li, Q. & Yuan, X. (2012). Cell death induced by 7-oxysterols via lysosomal and mitochondrial pathways is p53-dependent. Free Radical Biology & Medicine, 53(11), 2054-2061
Open this publication in new window or tab >>Cell death induced by 7-oxysterols via lysosomal and mitochondrial pathways is p53-dependent
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2012 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 53, no 11, p. 2054-2061Article in journal (Refereed) Published
Abstract [en]

Oxysterol accumulation and p53 expression mainly in macrophages have been associated with cell death and necrotic core formation in human atheroma progression. Oxidative stress and lysosomal membrane permeabilization (LMP) in macrophages are important causes of macrophage apoptosis. However, it is not understood how p53 and oxysterols interact in the process. We show here that 7-oxysterols induce endogenous full-length p53 and phospho-p53 (p53-Ser15) in both nucleus and cytoplasm of THP1 and J774 cells, which is followed by cellular oxidative stress and apoptotic cell death. The role of p53 in 7-oxysterol-mediated cell death is further investigated in temperature sensitive p53-transfected (M1-t-p53) and in p53-deficient (M1) cells. These results reveal that 7-oxysterols induce induction and nuclear translocation of p53 in M1-t-p53 cells, which in turn enhances LMP, mitochondrial translocation of Bax, mitochondrial membrane permeabilization, cytosolic release of cytochrome c, and cell death. Most importantly, the above effects of 7-oxysterols were not observed in p53-deficient M1 cells. The findings reveal that 7-oxysterol-induced cell death occurs via p53-dependent pathways. Subsequent p53 nuclear translocation and induction of wild-type and phosphorylated p53 are early steps in oxysterol-induced lysosomal-mitochondrial pathways involved in cell death.

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
Apoptosis, Atherosclerosis, Bax, Lysosomes, Mitochondria, Oxidative stress, Free radicals
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86892 (URN)10.1016/j.freeradbiomed.2012.09.007 (DOI)000312058300007 ()
Note

Funding Agencies|Swedish Heart Lung Foundation||Torsten and Ragnar Soderbergs Foundation||Stroke Foundation||Olle Engkvist Foundation||Swedish Gamla Tjanarinnor Foundation||Linkoping University||Linkoping University Hospital||

Available from: 2013-01-07 Created: 2013-01-07 Last updated: 2017-12-06
Laskar, A., Ghosh, M., Iqbal Khattak, S., Li, W. & Yuan, X.-M. (2012). Degradation of superparamagnetic iron oxide nanoparticle-induced ferritin by lysosomal cathepsins and related immune response. Nanomedicine, 7(5), 705-717
Open this publication in new window or tab >>Degradation of superparamagnetic iron oxide nanoparticle-induced ferritin by lysosomal cathepsins and related immune response
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2012 (English)In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 7, no 5, p. 705-717Article in journal (Refereed) Published
Abstract [en]

Aim: To examine the physiological impact of superparamagnetic iron oxide nanoparticles (SPIONs) on cell function and its interaction with oxysterol laden cells. Materials andamp; methods: Intracellular iron was determined by Prussian blue staining. Cellular ferritin, cathepsin L and ferroportin were analyzed by flow cytometry and fluorescence microscopy. Cytokine secretion was determined by ELISA and immunoblotting. Results: In U937 and THP 1 cells, we did not detect any loss of cell viability on SPION loading. Desferrioxamine prevents induction of both ferritin and cathepsin L by SPIONs. Inhibition of lysosomal cathepsins upregulates both endogenous- and SPION-induced ferritin. SPION loading induces membranous ferroportin and incites secretion of ferritin, TNF-alpha and IL-10. 7 beta-hydroxycholesterol exposure reduces SPION uptake by cells. Conclusion: SPION loading results in upregulation of lysosomal cathepsin, membranous ferroportin and ferritin degradation, which is associated with secretion of both pro- and anti-inflammatory cytokines. A reduced SPION uptake by oxysterol-laden cells may lead to a compromised MRI with elevated cathepsins and ferritin.

Place, publisher, year, edition, pages
Future Medicine, 2012
Keywords
atherosclerosis, cytokine, degradation, iron, lysosomal, monocyte, nanoparticle
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-78580 (URN)10.2217/nnm.11.148 (DOI)000304238300016 ()
Note

Funding Agencies|Swedish Heart Lung Foundation||research fund of Torsten och Ragnar Soderbergs||research fund of Stroke||research fund of Gamla Tjanarinnor||Linkoping University Hospital||

Available from: 2012-06-15 Created: 2012-06-15 Last updated: 2017-12-07
Han, Y., Zhang, Y., Yang, L.-h., Mi, X.-y., Dai, S.-d., Li, Q.-c., . . . Wang, E.-h. (2012). X-radiation inhibits histone deacetylase 1 and 2, upregulates Axin expression and induces apoptosis in non-small cell lung cancer. Radiation Oncology, 7(183)
Open this publication in new window or tab >>X-radiation inhibits histone deacetylase 1 and 2, upregulates Axin expression and induces apoptosis in non-small cell lung cancer
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2012 (English)In: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 7, no 183Article in journal (Refereed) Published
Abstract [en]

Background

Histone deacetylase (HDAC) plays an important role in the deacetylation of histone, which can alter gene expression patterns and affect cell behavior associated with malignant transformation. The aims of this study were to investigate the relationships between HDAC1, HDAC2, clinicopathologic characteristics, patient prognosis and apoptosis, to clarify the mechanism of upregulation of the Axis inhibitor Axin (an important regulator of the Wnt pathway) by X-radiation and to elucidate the effect of siRNA on radiation therapy of non-small cell lung cancer (NSCLC).

Methods

HDAC1 and HDAC2 expression levels were measured by immunohistochemistry and reverse transcription PCR. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling and fluorescence activated cell sorting. BE1 cells expressing Axin were exposed to 2 Gy of X-radiation.

Results

Expression of HDAC1 and that of HDAC2 were correlated, and significantly higher in NSCLC tissues than in normal lung tissues (P < 0.05). HDAC1 and HDAC2 expression was correlated with pTNM stage and negatively correlated with differentiation of NSCLC and apoptotic index (P < 0.05). The prognosis of patients with low expression of HDAC1 and HDAC2 was better than that of those with high expression. X-radiation and siRNA inhibited HDAC1 and HDAC2 expression in NSCLC cells and Axin levels were significantly higher in BE1 cells.

Conclusions

X-radiation and siRNA inhibit expression of HDAC1 and HDAC2, weaken the inhibitory effect of HDAC on Axin, upregulate Axin expression and induce apoptosis of lung cancer cells. Inhibition of HDAC1 and HDAC2 is a means of enhancing the radiosensitivity of NSCLC.

Place, publisher, year, edition, pages
BioMed Central, 2012
Keywords
HDAC1; HDAC2; Axin; Lung neoplasm; Radiosensitization
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-88759 (URN)10.1186/1748-717X-7-183 (DOI)000313972100002 ()
Available from: 2013-02-18 Created: 2013-02-18 Last updated: 2017-12-06
Li, W., Ghosh, M., Eftekhari, S. & Yuan, X. (2011). Lipid accumulation and lysosomal pathways contribute to dysfunction and apoptosis of human endothelial cells caused by 7-oxysterols. Biochemical and Biophysical Research Communications - BBRC, 409(4), 711-716
Open this publication in new window or tab >>Lipid accumulation and lysosomal pathways contribute to dysfunction and apoptosis of human endothelial cells caused by 7-oxysterols
2011 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 409, no 4, p. 711-716Article in journal (Refereed) Published
Abstract [en]

Endothelial dysfunction and cell death play an important role in pathogenesis of atherosclerosis. 7-Oxysterols, the major cytotoxic component found in oxidized low-density lipoprotein, are toxic to endothelial cells. However, the pathways and molecular mechanism involved in the process remain incompletely understood. In this study, we first investigate whether 7 beta-hydroxycholesterol (7 beta OH) or 7-ketocholesterol (7keto) induces apoptosis of human endothelial cell line (HUVEC-CS). We then examine possible involved pathways by focusing on cellular lipid, lysosomal pathways, cellular oxidative stress and mitochondrial pathways. Our results for the first time showed that 7-oxysterols induced apoptotic cell death of HUVEC-CS after 24 h, which was preceded by early lipid accumulation (6 h) and lysosomal membrane permeabilization (6-12 h). Afterward, levels of reactive oxygen species, mitochondrial membrane permeabilization, and lysosomal cathepsin were increased assayed by immuno-cytochemistry and blotting. Notably, the exposure to 7 beta OH or 7keto induced expressions and secretion of isoforms of von Willebrand factor (VWF). We conclude that apoptosis of HUVEC-CS induced by 7 beta OH or 7keto mediates by early lysosomal lipid accumulation and oxidative lysosomal pathways, which results in induction and release of VWF. The results suggest the cell death induced by 7-oxysterols may contribute to endothelial dysfunction and atherothrombosis.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam, 2011
Keywords
Atherosclerosis; Apoptosis; Oxidized lipids; Oxidative stress
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-69855 (URN)10.1016/j.bbrc.2011.05.071 (DOI)000292358500021 ()21621514 (PubMedID)
Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2018-01-12
Ghosh, M., Carlsson, F., Laskar, A., Yuan, X. & Li, W. (2011). Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages. FEBS Letters, 585(4), 623-9
Open this publication in new window or tab >>Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages
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2011 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 585, no 4, p. 623-9Article in journal (Refereed) Published
Abstract [en]

Moderate lysosomal membrane permeabilization (LMP) is an important inducer of apoptosis. Macrophages are professional scavengers and are rich in hydrolytic enzymes and iron. In the present study, we found that LMP by lysosomotropic detergent MSDH resulted in early up-regulation of lysosomal cathepsins, oxidative stress and ferritin up-regulation, and cell death. Lysosomotropic base NH(4)Cl reduced the ferritin induction and oxidative stress in apoptotic cells induced by MSDH. Cysteine cathepsin inhibitors significantly protected cell death and oxidative stress, but had less effect on ferritin induction. We conclude that oxidative stress induced by lysosomal rupture causes ferritin induction with concomitant mitochondrial damage, which are the potential target for prevention of cellular oxidative stress and cell death induced by typical lysosomotropic substances in different disorders.

Place, publisher, year, edition, pages
Elsevier, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-65820 (URN)10.1016/j.febslet.2010.12.043 (DOI)000287237100007 ()21219901 (PubMedID)
Available from: 2011-02-21 Created: 2011-02-21 Last updated: 2017-12-11Bibliographically approved
Laskar, A., Yuan, X. & Li, W. (2010). Dimethyl Sulfoxide Prevents 7 beta-Hydroxycholesterol-Induced Apoptosis by Preserving Lysosomes and Mitochondria. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 56(3), 263-267
Open this publication in new window or tab >>Dimethyl Sulfoxide Prevents 7 beta-Hydroxycholesterol-Induced Apoptosis by Preserving Lysosomes and Mitochondria
2010 (English)In: JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, ISSN 0160-2446, Vol. 56, no 3, p. 263-267Article in journal (Refereed) Published
Abstract [en]

Dimethyl sulfoxide (DMSO) is a widely used vehicle for water-insoluble substances and exerts a wide range of pharmacologic effects including anti-inflammatory and free radical scavenging properties. Additionally, in an animal model, DMSO inhibited cholesterol- induced atherosclerosis. Despite such profound pharmacologic effects, mechanisms at the cellular level are not well understood. Atherogenic oxysterols, especially 7-oxysterols, are potent inducers of oxidative stress, cell apoptosis, and are elevated in human atherosclerotic lesions. In this study, we first investigated the effect of DMSO on 7 beta-hydroxycholesterol-induced apoptosis of U937 cells and then focused on its influences on production of reactive oxygen species, lysosomal, and mitochondrial membrane permeability. Our results revealed that DMSO protected U937 cells against 7 beta-hydroxycholesterol- induced cell death by preventing lysosomal and mitochondrial membrane permeabilization and reactive oxygen species production. Our results also emphasize the necessity for appropriate solvent control groups in experimental models in which DMSO has been used to examine drug effect or identify pathways.

Place, publisher, year, edition, pages
Raven Press Publishers, 2010
Keywords
7 beta-hydroxycholesterol, oxidative stress, apoptosis, dimethyl sulfoxide
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-60702 (URN)10.1097/FJC.0b013e3181eb3063 (DOI)000281846200008 ()
Available from: 2010-11-01 Created: 2010-10-22 Last updated: 2014-01-17Bibliographically approved
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