Publications by authors named "Yanjiang Xing"

12 Publications

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The LPS induced pyroptosis exacerbates BMPR2 signaling deficiency to potentiate SLE-PAH.

FASEB J 2021 Dec;35(12):e22044

Institute of Basic Medical Sciences, School of Basic Medicine Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Pulmonary arterial hypertension (PAH) is a common and fatal complication of systemic lupus erythematosus (SLE). Whether the BMP receptor deficiency found in the genetic form of PAH is also involved in SLE-PAH patients remains to be identified. In this study, we employed patient-derived samples from SLE-associated PAH (SLE-PAH) and established comparable mouse models to clarify the role of BMP signaling in the pathobiology of SLE-PAH. Firstly, serum levels of LPS and autoantibodies (auto-Abs) directed at BMP receptors were significantly increased in patients with SLE-PAH compared with control subjects, measured by ELISA. Mass cytometry was applied to compare peripheral blood leukocyte phenotype in patients prior to and after treatment with steroids, which demonstrated inflammatory cells alteration in SLE-PAH. Furthermore, BMPR2 signaling and pyroptotic factors were examined in human pulmonary arterial endothelial cells (PAECs) in response to LPS stimulation. Interleukin-8 (IL-8) and E-selectin (SELE) expressions were up-regulated in autologous BMPR2 endothelial cells and siBMPR2-interfered PAECs. A SLE-PH model was established in mice induced with pristane and hypoxia. Moreover, the combination of endothelial specific BMPR2 knockout in SLE mice exacerbated pulmonary hypertension. Pyroptotic factors including gasdermin D (GSDMD) were elevated in the lungs of SLE-PH mice, and the pyroptotic effects of serum samples isolated from SLE-PAH patients on PAECs were analyzed. BMPR2 signaling upregulator (BUR1) showed anti-pyroptotic effects in SLE-PH mice and PAECs. Our results implied that deficiencies of BMPR2 signaling and proinflammatory factors together contribute to the development of PAH in SLE.
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http://dx.doi.org/10.1096/fj.202100851RRDOI Listing
December 2021

Autoimmunity in Pulmonary Arterial Hypertension: Evidence for Local Immunoglobulin Production.

Front Cardiovasc Med 2021 21;8:680109. Epub 2021 Sep 21.

State Key Laboratory of Medical Molecular Biology, Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.

Pulmonary arterial hypertension (PAH) is a progressive life-threatening disease. The notion that autoimmunity is associated with PAH is widely recognized by the observations that patients with connective tissue diseases or virus infections are more susceptible to PAH. However, growing evidence supports that the patients with idiopathic PAH (IPAH) with no autoimmune diseases also have auto-antibodies. Anti-inflammatory therapy shows less help in decreasing auto-antibodies, therefore, elucidating the process of immunoglobulin production is in great need. Maladaptive immune response in lung tissues is considered implicating in the local auto-antibodies production in patients with IPAH. In this review, we will discuss the specific cell types involved in the lung immune response, the potential auto-antigens, and the contribution of local immunoglobulin production in PAH development, providing a theoretical basis for drug development and precise treatment in patients with PAH.
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http://dx.doi.org/10.3389/fcvm.2021.680109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490641PMC
September 2021

Evidence of Accumulated Endothelial Progenitor Cells in the Lungs of Rats with Pulmonary Arterial Hypertension by Zr-oxine PET Imaging.

Mol Ther Methods Clin Dev 2020 Jun 3;17:1108-1117. Epub 2020 May 3.

State Key Laboratory of Medical Molecular Biology, Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100730, China.

Endothelial progenitor cells (EPCs) play a major role in regulating pulmonary vascular remodeling during pulmonary arterial hypertension (PAH) development. Several preclinical and clinical trials of EPCs transplantation have been performed for the treatment of PAH. However, there is no reliable method to monitor real-time cell trafficking and quantify transplanted EPCs. Here in this paper we isolated EPCs from human peripheral blood, identified their functional integrity, and efficiently labeled the EPCs with Zr-oxine and DiO. Labeled EPCs were injected into the tail vein of normal and PAH rats to be tracked . From the microPET/CT images, we found EPCs were distributed primarily in the lung at 1 h and then migrated to the liver and spleen. We could observe the 3,3' dioctadecyloxacarbocyanine perchlorate (DiO)-labeled EPCs binding in the pulmonary vasculature by CellVizio confocal. The result of quantitative analysis revealed significantly higher accumulation of EPCs in the lungs of PAH rats than in those of healthy rats. The distribution and higher accumulation of EPCs in the lungs of PAH rats could help to evaluate the safety and provide evidence of effectiveness of EPC therapy.
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http://dx.doi.org/10.1016/j.omtm.2020.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256434PMC
June 2020

A novel piperidine identified by stem cell-based screening attenuates pulmonary arterial hypertension by regulating BMP2 and PTGS2 levels.

Eur Respir J 2018 04 4;51(4). Epub 2018 Apr 4.

State Key Laboratory of Medical Molecular Biology, Dept of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.

Genetic defects in bone morphogenetic protein type II receptor (BMPRII) signalling and inflammation contribute to the pathogenesis of pulmonary arterial hypertension (PAH). The receptor is activated by bone morphogenetic protein (BMP) ligands, which also enhance transcription. A small-molecule BMP upregulator with selectivity on vascular endothelium would be a desirable therapeutic intervention for PAH.We assayed compounds identified in the screening of BMP2 upregulators for their ability to increase the expression of inhibitor of DNA binding 1 (Id1), using a dual reporter driven specifically in human embryonic stem cell-derived endothelial cells. These assays identified a novel piperidine, BMP upregulator 1 (BUR1), that increased endothelial Id1 expression with a half-maximal effective concentration of 0.098 μmol·L Microarray analyses and immunoblotting showed that BUR1 induced BMP2 and prostaglandin-endoperoxide synthase 2 (PTGS2) expression. BUR1 effectively rescued deficient angiogenesis in autologous endothelial cells generated by CRISPR/Cas9 and patient cells.BUR1 prevented and reversed PAH in monocrotaline rats, and restored BMPRII downstream signalling and modulated the arachidonic acid pathway in the pulmonary arterial endothelium in the Sugen 5416/hypoxia PAH mouse model.In conclusion, using stem cell technology we have provided a novel small-molecule compound which regulates BMP2 and PTGS2 levels that might be useful for the treatment of PAH.
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http://dx.doi.org/10.1183/13993003.02229-2017DOI Listing
April 2018

CCL11-induced eosinophils inhibit the formation of blood vessels and cause tumor necrosis.

Genes Cells 2016 Jun 12;21(6):624-38. Epub 2016 May 12.

Department of Cell Science, Faculty of Graduate School of Science and Technology, Niigata University, Nishi-ku, Niigata, 950-2181, Japan.

We previously demonstrated that IL-18 and CCL11 were highly expressed in an NFSA tumor cell line that showed limited angiogenesis and severe necrosis. However, IL-18 was not responsible for the immune cell accumulation and necrosis. Here, we attempted to clarify the relevance of CCL11 in angiogenesis and tumor formation. We established CCL11-overexpressing MS-K cell clones (MS-K-CCL11) to assess the role of CCL11 in immune cell accumulation and angiogenesis. The MS-K-CCL11 cells did not form tumors in mice. MS-K-CCL11-conditioned medium (CM) and recombinant CCL11 induced macrophage and eosinophil differentiation from bone marrow cells. The MS-K-CCL11-CM effectively recruited the differentiated eosinophils. Furthermore, the eosinophils damaged the MS-K, NFSA and endothelial cells in a dose-dependent manner. Administration of an antagonist of CCR3, a CCL11 receptor, to NFSA tumor-bearing mice restored the blood vessel formation and blocked the eosinophil infiltration into the NFSA tumors. Furthermore, other CCL11-overexpressing LM8 clones were established, and their tumor formation ability was reduced compared to the parental LM8 cells, accompanied by increased eosinophil infiltration, blockade of angiogenesis and necrosis. These results indicate that CCL11 was responsible for the limited angiogenesis and necrosis by inducing and attracting eosinophils in the tumors.
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http://dx.doi.org/10.1111/gtc.12371DOI Listing
June 2016

Inhibition of blood vessel formation in tumors by IL-18-polarized M1 macrophages.

Genes Cells 2016 Mar 21;21(3):287-95. Epub 2016 Jan 21.

Department of Cell Science, Faculty of Graduate School of Science and Technology, Niigata University, Niigata, 950-2181, Japan.

We previously showed that interleukin (IL)-18 produced by NFSA cells induced the M1 type of macrophages in NFSA tumors, caused the destruction of endothelial cells in vitro and may have resulted in the necrosis of NFSA tumors by enhancing macrophage phagocytosis and cytotoxicity. However, the effect of IL-18 on blood vessel formation in vivo has not been elucidated. MS-K cells do not express il-18, and they form tumors with well-developed blood vessels. Here, we established IL-18-over-expressing MS-K cell clones (MS-K-IL-18) to address the roles of IL-18 in angiogenesis. The over-expression of IL-18 inhibited the proliferation rate of the MS-K-IL-18 cells in vitro and blood vessel formation in the MS-K-IL-18 tumors. Interestingly, CD14-positive cells from the MS-K-IL-18 tumor had up-regulated expression of the M1-type macrophage marker il-6 and down-regulated expression of interferon (ifn)-γ. Furthermore, FACS analysis showed more accumulation of CD11b+/CD80+ M1 macrophages in the MS-K-IL-18 tumors than in the parental MS-K tumor. Moreover, an in vitro coculture assay showed that MS-K-IL-18-conditioned medium (CM) stimulated macrophages to induce the apoptosis of endothelial cells. Cumulatively, our data showed that IL-18 inhibited tumor blood vessel formation in vivo.
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http://dx.doi.org/10.1111/gtc.12329DOI Listing
March 2016

Role of FGF10 on tumorigenesis by MS-K.

Genes Cells 2014 Feb 10;19(2):112-25. Epub 2013 Dec 10.

Department of Cell Science, Faculty of Graduate School of Science and Technology, Niigata University, Nishi-ku, Niigata, 950-2181, Japan.

Murine MS-K and NFSA cell lines formed tumor after inoculation into mouse and both cell lines expressed high level of vascular endothelial growth factor-A (vegf-A) and produced same level of VEGF-A. However, poor blood vessel formation, and necrosis was significantly observed in NFSA-tumor, contrary to well-developed blood vessel formation in MS-K tumor. The microarray analysis showed high expression of fibroblast growth factor-10 (fgf-10) in MS-K than NFSA. In this report, the role of fgf-10 on tumor growth was studied. MS-K enhanced more proliferation of endothelial cells by direct co-culture than NFSA, and rFGF10 supported the proliferation of HUVEC in combination with VEGF-A. fgf-10-knocked down MS-K, MS-K (fgf-10-KD), proliferated slower in vitro and the tumorigenicity of them was also slower than control. The blood vessel formation in these MS-K (fgf-10-KD) clones was reduced compared with the MS-K (normal). qPCR analysis showed the suppression of vegf-A, vegf-C and fgfr-1-expression in the MS-K (fgf-10-KD) clones. Taken together, these results indicated that FGF10, which was produced from tumor cells, was essential for the proliferation of tumor cell itself and also supports proliferation of endothelial cells. Thus, FGF10 plays an important role for tumor growth by both paracrine and autocrine manner.
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http://dx.doi.org/10.1111/gtc.12118DOI Listing
February 2014

Enhancement of phagocytosis and cytotoxicity in macrophages by tumor-derived IL-18 stimulation.

BMB Rep 2014 May;47(5):286-91

Department of Cell Science, Faculty of Graduate School of Science and Technology, Niigata University, Nishi-ku, Niigata 950-2181, Japan.

Inoculation of mice with the murine NFSA cell line caused the formation of large tumors with necrotic tumor cores. FACS analysis revealed accumulations of CD11b(+) cells in the tumors. Microarray analysis indicated that the NFSA cells expressed a high level of the pro-inflammatory factor interleukin-18 (il-18), which is known to play a critical role in macrophages. However, little is known about the physiological function of IL-18-stimulated macrophages. Here, we provide direct evidence that IL-18 enhances the phagocytosis of RAW264 cells and peritoneal macrophages, accompanied by the increased expression of tumor necrosis factor (tnf-α), interleukin-6 (il-6) and inducible nitric oxide synthase (Nos2). IL-18-stimulated RAW264 cells showed an enhanced cytotoxicity to endothelial F-2 cells via direct cell-to-cell interaction and the secretion of soluble mediators. Taken together, our results demonstrate that tumor-derived IL-18 plays an important role in the phagocytosis of macrophages and that IL-18-stimulated macrophages may damage tumor endothelial cells.
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http://dx.doi.org/10.5483/bmbrep.2014.47.5.152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163866PMC
May 2014

miR-370 is stage-specifically expressed during mouse embryonic development and regulates Dnmt3a.

FEBS Lett 2013 Mar 8;587(6):775-81. Epub 2013 Feb 8.

School of Life Science and Biotechnology, Harbin Institute of Technology, No 92 West Da-zhi Street, Harbin, Heilongjian 150001, China.

MicroRNAs (miRNAs) are small non-coding RNAs that participate in a large variety of biological processes. In this paper, the spatiotemporal expression pattern of miR-370 was characterized during mouse embryonic development, and was found to be stage- and tissue-specifically expressed. In addition, through luciferase reporter assays and western blot analyses, DNA methyltransferase 3A (Dnmt3a) was identified as a directly regulated target of miR-370. Altogether, our results indicate that miR-370 may play important roles in the morphogenesis of diverse organs, especially brain and adrenal glands, by mediating Dnmt3a expression during mouse development.
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http://dx.doi.org/10.1016/j.febslet.2013.01.070DOI Listing
March 2013

Expression patterns of ubiquitin conjugating enzyme UbcM2 during mouse embryonic development.

Gene Expr 2012 ;15(4):163-70

School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Heilongjiang, China.

Ubiquitin conjugating enzyme UbcM2 (Ubiquitin-conjugating enzymes from Mice, the number reveals the identification order) has been implicated in many critical processes, such like growth-inhibiting, mediating cell proliferation and regulation of some transcription factor, but the expression profile during mouse embryo development remains unclear. Hereby, during mid-later embryonic stage, the expression patterns of UbcM2 were examined using in situ hybridization and quantitative real-time PCR (qRT-PCR). The signals were significantly intense in central nervous system and skeletal system, weak in tongue, heart, lung, liver, and kidney. In the central nervous system, UbcM2 was principally expressed in thalamus, external germinal layer of cerebellum (EGL), mitral cell layer of olfactory bulb, hippocampus, marginal zone and ventricular zone of cerebral cortex, and spinal cord. In the skeletal system, UbcM2 was primarily expressed in proliferating cartilage. Furthermore, qRT-PCR analysis displayed that the expression of UbcM2 was ubiquitous at E15.5, most prominent in brain, weaker in lung liver and kidney, accompanied by the lowest level in tongue and heart. During brain development, the expression level of UbcM2 first ascended and then decreased from E12.5 to E18.5, the peak of which sustained starting at E14.5 until E16.5. Together, these results suggest that UbcM2 may play potential roles in the development of mouse diverse tissues and organs, particularly in the development of brain and skeleton.
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http://dx.doi.org/10.3727/105221612x13372578119616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043840PMC
August 2012

Expression patterns of imprinted gene Inpp5f-v3 during mouse brain development.

J Mol Histol 2011 Apr 20;42(2):167-73. Epub 2011 Mar 20.

Department of Life Science and Engineering, Harbin Institute of Technology, No. 92 West Da-zhi Street, Harbin, 150001, Heilongjian, China.

Inpp5f-v3 is a transcriptional variant of Inpp5f (inositol polyphosphate-5-phosphatase F) and locates in distal mouse chromosome 7. It is a paternally expressed imprinted gene in mouse. In this study, we examined the spatiotemporal patterns of Inpp5f-v3 gene during the mouse development. The northern blotting analysis revealed that only one transcript approx 2.7 kb of Inpp5f-v3 was detected in brain. The signals were only observed in brain by the whole-mount in situ hybridization at embryonic day 11.5 (E11.5). The results of quantitative real-time PCR (QRT-PCR) showed that the expression of Inpp5f-v3 increased gradually from the E11.5 to E17.5 and reached the highest at E17.5, then decreased at E18.5 during the brain development. Inpp5f-v3 gene was strongly expressed in the cerebral cortex, olfactory bulb, external germinal layer of cerebellum and ventricular zone (Vz) during the embryonic development (E15.5-E19.5), whereas the expression increased in the olfactory bulb and the cerebellum after birth by using in situ hybridization. The results also demonstrated that the expression of Inpp5f-v3 gene mainly located in olfactory bulb and hippocampus at postnatal day 7 (P7) and adulthood. These results suggest that Inpp5f-v3 is specifically expressed in mouse brain, and may function in the development of mouse brain.
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http://dx.doi.org/10.1007/s10735-011-9321-yDOI Listing
April 2011

Expression of non-coding RNA AB063319 derived from Rian gene during mouse development.

J Mol Histol 2011 Apr 9;42(2):105-12. Epub 2011 Feb 9.

State Key Laboratory of Urban Water Resource and Environment, Department of Life Science and Engineering, Harbin Institute of Technology, No. 92 West Da-zhi Street, 150001, Harbin, Heilongjiang, China.

The regulatory functions of many non-coding RNAs (ncRNAs) were widely recognized. However, there are very few publications on long intronic ncRNAs. The transcriptional hierarchy driving a large amount of long and short ncRNAs originated from the maternal chromosome is not clarified in the Dlk1-Dio3 imprinted clusters of mouse distal chromosome 12. Here, we only focused on the previously identified long ncRNA AB063319 which derives from the large imprinted gene Rian and contains three retained introns of Rian, and tried to unsderstand this ncRNAs part of biological functions. We used in situ hybridization and quantitative real-time RT-PCR (QRT-PCR) to characterize the spatiotemporal expression pattern of AB063319 during mouse development. The in situ hybridization results showed that AB063319 was prominently expressed in the brain at embryonic day 10.5 (E10.5) and E11.5, and abundantly expressed in brain, muscle, liver, lung and neuroendocrine tissues at E15.5. Furthermore, quantitative analyses results showed that AB063319 was gradually up-regulated from E9.5 to E18.5 and down-regulated at E19.5 during the mouse embryonic development, and AB063319 was highly expressed in tongue and brain at E12.5, E15.5 and E18.5. Alternatively, AB063319 expression was also predominantly detected in tongue and brain at mouse postnatal day 6 (P6) by semi-quantitative RT-PCR. These results indicated that AB063319, as a stable transcriptional ncRNA, might play the important roles in the morphogenesis of diverse organs and tissues, especially associated with brain and muscle development at mouse embryonic and postnatal stages.
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http://dx.doi.org/10.1007/s10735-011-9312-zDOI Listing
April 2011
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