Publications by authors named "Zixuan Sun"

21 Publications

  • Page 1 of 1

HucMSC exosome-delivered 14-3-3ζ alleviates ultraviolet radiation-induced photodamage via SIRT1 pathway modulation.

Aging (Albany NY) 2021 Apr 21;13(8):11542-11563. Epub 2021 Apr 21.

Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, People's Republic of China.

Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) are nano-sized membrane-bound vesicles that have been reported to facilitate skin regeneration and repair. However, the roles played by hucMSC-ex in ultraviolet (UV) radiation-induced skin photodamage and the underlying mechanisms remain unknown. To investigate the functions of hucMSC-ex in a rat model of acute skin photodamage, immunofluorescence and immunohistochemical staining, quantitative real-time-polymerase chain reaction (qRT-PCR), western blot, and gene silencing assays were performed. We found that the subcutaneous injection of hucMSC-ex elicited antioxidant and anti-inflammatory effects against UV radiation-induced DNA damage and apoptosis. Further studies showed that the sirtuin 1 (SIRT1) expression level in skin keratinocytes (HaCaT) decreased in a time- and dose-dependent manner under UV radiation induced-oxidative stress conditions, which could be reversed by treatment with hucMSC-ex. The activation of SIRT1 significantly attenuated UV- and HO-induced cytotoxic damage by inhibiting oxidative stress and promoting the activation of autophagy. Our study found that 14-3-3ζ protein, which was delivered by hucMSC-ex, exerted a cytoprotective function via the modulation of a SIRT1-dependent antioxidant pathway. Collectively, our findings indicated that hucMSC-ex might represent a new potential agent for preventing or treating UV radiation-induced skin photodamage and aging.
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http://dx.doi.org/10.18632/aging.202851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109102PMC
April 2021

Platelet-rich plasma promotes MSCs exosomes paracrine to repair acute kidney injury via AKT/Rab27 pathway.

Am J Transl Res 2021 15;13(3):1445-1457. Epub 2021 Mar 15.

Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University Zhenjiang 212013, Jiangsu, China.

Acute kidney injury (AKI) is defined by rapid deterioration of renal function, and is a common complication in hospitalized patients. Among the recent therapeutic options, mesenchymal stem cells (MSCs) are considered a promising therapeutic strategy for damaged tissue repair. Platelet rich plasma (PRP) regulates mesenchymal cells to repair tissue damage through the release of growth factors. In this study, we proposed a possible therapeutic use of MSCs stimulated by platelet-rich plasma (PRP-MSCs) in a glycerin-induced AKI murine model. and studies, showed that PRP-MSCs could significantly attenuate serum blood urea nitrogen and creatinine levels, and reverse the histopathological kidney damage. PRP-MSCs treatment reduced renal tubular cell apoptosis stimulated by glycerin. We confirmed that PRP promoted the proliferation and reinforced the stemness of MSCs by inducing YAP nucleus expression, and that PRP promoted MSCs exosomes in a paracrine manner to repair AKI through an activated AKT/Rab27 pathway. Our results revealed that the PRP stimulated MSCs paracrine pathway could effectively alleviate glycerin-induced AKI. Therefore, PRP pretreatment may be a new method to improve the therapeutic effect of MSCs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014389PMC
March 2021

Circular RNA ITCH suppresses metastasis of gastric cancer via regulating miR-199a-5p/Klotho axis.

Cell Cycle 2021 Mar-Mar;20(5-6):522-536. Epub 2021 Jan 27.

Aoyang Institute of Cancer, Jiangsu University, Suzhou, China.

Circular RNAs (circRNAs) are considered as a new regulatory factor in growth, metastasis and therapeutic resistance of human cancers. But the clinical significance and underlying mechanism of circular RNA ITCH (circ-ITCH) in gastric cancer (GC) remain unknown. In the present study, we found that circ-ITCH was down-regulated in GC cell lines, GC tissues and their serum-derived exosomes. The level of circ-ITCH was related to invasion depth. Functional assays showed that circ-ITCH overexpression inhibited the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) of GC cells, whereas circ-ITCH knockdown appeared an opposite effect. Bioinformatic analysis and luciferase reporter assay confirmed that circ-ITCH acted as miR-199a-5p sponge and increased the level of Klotho. The expression level of miR-199-5p was up-regulated in GC tissues and negatively correlated with that of circ-ITCH. MiR-199a-5p mimics reversed the effects on inhibiting metastasis induced by circ-ITCH overexpression and decreased the level of Klotho in GC cells. Our findings indicate that circ-ITCH suppresses metastasis of GC by acting as the sponge of miR-199a-5p and increasing Klotho expression, which serves as a potential biomarker and targets for the diagnosis and therapy of GC. CircRNAs: circular RNAs; GC: gastric cancer; circ-ITCH: circular RNA Itchy E3 ubiquitin protein ligase; ceRNA: competitive endogenous RNA; EMT: Epithelial-mesenchymal transition; siRNA: Small interfering RNA; TEM: transmission electron microscope; NTA: nanoparticle tracking analysis.
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http://dx.doi.org/10.1080/15384101.2021.1878327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018440PMC
January 2021

Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Accelerate Cutaneous Wound Healing by Enhancing Angiogenesis through Delivering Angiopoietin-2.

Stem Cell Rev Rep 2021 Apr;17(2):305-317

Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application, School of Medicine, Jiangsu University, 301 Xuefu Road, 212013, Zhenjiang, Jiangsu, People's Republic of China.

The underlying mechanisms of human umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes (hucMSC-Exs), which play significant roles in skin wound healing, remain poorly understood. By using a rat model of deep second-degree burn injury, the roles of hucMSC-Exs in angiogenesis and cutaneous wound healing in vivo were investigated. We found that hucMSC-Exs accelerated skin wound healing and angiogenesis, inducing a higher wound-closure rate and increased expression of CD31 in vivo. We also discovered that hucMSC-Exs contained angiopoietin-2 (Ang-2), and treatment with hucMSC-Exs enhanced the expression of the Ang-2 protein in the wound area and human umbilical vein endothelial cells (HUVECs) through exosomal-mediated Ang-2 transfer. Moreover, hucMSC-Exs promoted the proliferative, migratory, and tube-forming ability of HUVECs. Furthermore, overexpression of Ang-2 in hucMSC-Exs further enhanced HUVEC migration and tube formation and exerted therapeutic and proangiogenic effects in cutaneous wounds in rats, whereas knockdown of Ang-2 in hucMSC-Exs abrogated these therapeutic and proangiogenic effects. Taken together, our results indicated that hucMSC-Ex-derived Ang-2 plays a significant role in tube formation of HUVECs and promotion of angiogenesis, and further suggested that hucMSC-Ex-based therapy may serve as a promising therapeutic approach for promoting cutaneous wound healing.
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http://dx.doi.org/10.1007/s12015-020-09992-7DOI Listing
April 2021

Gastric-cancer-derived mesenchymal stem cells: a promising target for resveratrol in the suppression of gastric cancer metastasis.

Hum Cell 2020 Jul 29;33(3):652-662. Epub 2020 Apr 29.

AoYoung Cancer Research Institute, Jiangsu University, Zhangjiagang, 215618, Jiangsu, China.

The tumor microenvironment (TM) is an essential factor of tumor progression. Mesenchymal stem cells (MSCs) are important components of the TM and play critical roles in cancer metastasis. Resveratrol (RES) is a potential antitumor drug that has attracted extensive attention. However, it remains unclear whether RES can exert its antitumor activity by targeting MSCs located in the TM. In this study, we demonstrated that the conditioned medium of gastric-cancer-derived MSCs (GC-MSCs) promoted gastric cancer (GC) metastasis and facilitated the progression of epithelialmesenchymal transition (EMT) of GC cells. However, after pretreatment with RES, the prometastatic effect of GC-MSCs on GC cells was reversed. Furthermore, RES reduced GC-MSC (IL-6, IL-8, MCP-1, VEGF) gene expression and protein secretion, and counteracted the activation of the GC-MSC-induced Wnt/β-catenin signaling of GC cells, with less β-catenin nuclear transport and declined expression of β-catenin, CD44, and CyclinD3 in GC cells. Re-expression of β-catenin impaired the inhibitory effect of RES on GC cells. In conclusion, RES restricted the mobility increase of GC cells and reversed the progress of EMT induced by GC-MSCs by inactivating the Wnt/β-catenin signaling. GC-MSCs are promising target for RES in the inhibition of GC metastasis.
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http://dx.doi.org/10.1007/s13577-020-00339-5DOI Listing
July 2020

The role and mechanism of miR-374 regulating the malignant transformation of mesenchymal stem cells.

Am J Transl Res 2018 15;10(10):3224-3232. Epub 2018 Oct 15.

AoYoung Cancer Research Institute, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University Zhenjiang 212013, Jiangsu, P. R. China.

MicroRNAs (miRNAs) play important roles in cell transformation and carcinogenesis. We have previously established a tumor cell line K3 transformed from rat bone marrow-derived mesenchymal stem cells (rBM-MSCs). However, the underlying mechanism involved in MSC transformation remains unclear. Herein, we identified the key miRNAs that regulate the transformation of rBM-MSCs, and clarified their biological roles. Microarray and qRT-PCR results showed an increased expression of miR-374 but decreased expressions of miR-199a, miR-145, miR-34a, and miR-214 in K3 cells compared to rBM-MSCs. MiR-374 overexpression in rBM-MSCs increased the colony number and the proportion of the cells in S-phase. In addition, miR-374 overexpression reduced E-cadherin expression and increased N-cadherin expression in rBM-MSCs, promoting the migration ability of these cells. On the contrary, miR-374 knockdown in K3 cells led to impaired proliferation and migration capacities. Furthermore, was identified as a target gene of miR-374. MiR-374 overexpression upregulated β-catenin expression in rBM-MSCs while miR-374 knockdown downregulated that in K3 cells. In conclusion, miR-374 promotes the proliferation and migration of transformed MSCs by regulating Wnt5a/β-catenin signaling pathway, which provides evidence for the contribution of miRNA to MSC transformation and suggests a new role of miR-374 in cancer development and progression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220215PMC
October 2018

Exosomal TRIM3 is a novel marker and therapy target for gastric cancer.

J Exp Clin Cancer Res 2018 Jul 21;37(1):162. Epub 2018 Jul 21.

Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.

Background: Exosomes are critically involved in cancer development and progression. The exosomal contents have been suggested as ideal cancer biomarkers. In this study, we investigated the expression of exosomal proteins in the serum of gastric cancer patients and their roles in gastric cancer.

Methods: The proteomic profile of exosomes from the serum of gastric cancer patients was detected by using LC-MS/MS. The expression of TRIM3 in exosomes from the serum of gastric cancer patients and healthy controls was assessed by ELISA and western blot. Immunohistochemistry was used to detect TRIM3 expression in gastric cancer tissues and their matching adjacent tissues. The growth and migration abilities of gastric cancer cells with TRIM3 overexpression or knockdown in vitro were evaluated by colony formation assay and transwell migration assay. The effects of TRIM3 overexpression or knockdown on gastric cancer growth and metastasis in vivo were investigated by using subcutaneous xenograft tumor and peritoneal metastasis mouse model. The effects of TRIM3-overexpressing exosomes on gastric cancer growth and metastasis in vitro and in vivo were also evaluated.

Results: We found that the expression levels of TRIM3 mRNA and protein were decreased in gastric cancer tissues compared to the matched control tissues. In addition, the levels of TRIM3 protein in the serum exosomes of gastric cancer patients were lower than that in healthy controls. We demonstrated that TRIM3 overexpression reduced while TRIM3 knockdown promoted the growth and metastasis of gastric cancer in vitro and in vivo through the regulation of stem cell factors and EMT regulators. Moreover, exosomes-mediated delivery of TRIM3 protein could suppress gastric cancer growth and metastasis in vitro and in vivo.

Conclusions: Taken together, our findings suggest that exosomal TRIM3 may serve as a biomarker for gastric cancer diagnosis and the delivery of TRIM3 by exosomes may provide a new avenue for gastric cancer therapy.
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http://dx.doi.org/10.1186/s13046-018-0825-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054744PMC
July 2018

Exosomal miR-423-5p targets SUFU to promote cancer growth and metastasis and serves as a novel marker for gastric cancer.

Mol Carcinog 2018 09 23;57(9):1223-1236. Epub 2018 May 23.

Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.

Exosomes are critically involved in tumor growth, metastasis, and therapy resistance. Exosomes have the potential to be utilized as cancer biomarkers. In this study, we aimed to explore the roles and clinical values of exosomal miRNAs in gastric cancer. We found that the concentration of exosomes was significantly higher in the serum of gastric cancer patients and the culture supernatants of gastric cancer cells than that in healthy volunteers and gastric mucosa epithelial cells. In particular, miR-423-5p was elevated in the serum exosomes of gastric cancer patients, and the level of exosomal miR-423-5p was remarkably correlated with lymph node metastasis. High level of exosomal miR-423-5p was associated with poor outcome in gastric cancer patients. MiR-423-5p enriched exosomes could be internalized into gastric cancer cells, which enhanced cell proliferation and migration both in vitro and in vivo. Mechanistically, miR-423-5p inhibited the expression of suppressor of fused protein (SUFU) to enhance the proliferation and migration of gastric cancer cells. The expression levels of SUFU were significantly decreased in gastric cancer cells and the tumor tissues of gastric cancer patients. Taken together, our findings indicate that exosomes could deliver miR-423-5p to promote cancer growth and metastasis and serum exosomal miR-423-5p may serve as a potential marker for gastric cancer diagnosis and prognosis.
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http://dx.doi.org/10.1002/mc.22838DOI Listing
September 2018

Cancer stemness and metastatic potential of the novel tumor cell line K3: an inner mutated cell of bone marrow-derived mesenchymal stem cells.

Oncotarget 2017 Jun;8(24):39522-39533

Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, P. R. China.

Mesenchymal stem cells (MSCs) transplantation has been used for therapeutic applications in various diseases. Here we report MSCs can malignantly transform in vivo. The novel neoplasm was found on the tail of female rat after injection with male rat bone marrow-derived MSCs (rBM-MSCs) and the new tumor cell line, K3, was isolated from the neoplasm. The K3 cells expressed surface antigens and pluripotent genes similar to those of rBM-MSCs and presented tumor cell features. Moreover, the K3 cells contained side population cells (SP) like cancer stem cells (CSCs), which might contribute to K3 heterogeneity and tumorigenic capacity. To investigate the metastatic potential of K3 cells, we established the nude mouse models of liver and lung metastases and isolated the corresponding metastatic cell lines K3-F4 and K3-B6. Both K3-F4 and K3-B6 cell lines with higher metastatic potential acquired more mesenchymal and stemness-related features. Epithelial-mesenchymal transition is a potential mechanism of K3-F4 and K3-B6 formation.
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http://dx.doi.org/10.18632/oncotarget.17133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503629PMC
June 2017

A comprehensive experiment for molecular biology: Determination of single nucleotide polymorphism in human REV3 gene using PCR-RFLP.

Biochem Mol Biol Educ 2017 Jul 1;45(4):299-304. Epub 2017 Feb 1.

Department of Molecular Biology and Diagnostics, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.

Laboratory exercise is helpful for medical students to understand the basic principles of molecular biology and to learn about the practical applications of molecular biology. We have designed a lab course on molecular biology about the determination of single nucleotide polymorphism (SNP) in human REV3 gene, the product of which is a subunit of DNA polymerase ζ and SNPs in this gene are associated with altered susceptibility to cancer. This newly designed experiment is composed of three parts, including genomic DNA extraction, gene amplification by PCR, and genotyping by RFLP. By combining these activities, the students are not only able to learn a series of biotechniques in molecular biology, but also acquire the ability to link the learned knowledge with practical applications. This comprehensive experiment will help the medical students improve the conceptual understanding of SNP and the technical understanding of SNP detection. © 2017 by The International Union of Biochemistry and Molecular Biology, 45(4):299-304, 2017.
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http://dx.doi.org/10.1002/bmb.21037DOI Listing
July 2017

A novel bocavirus from domestic mink, China.

Virus Genes 2016 Dec 12;52(6):887-890. Epub 2016 Aug 12.

Blood Systems Research Institute, Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.

Bocaviruses have been found in the feces of humans and a variety of animals, including pigs, cattle, dogs, gorillas, cats, and sea lions. Here, we have characterized the almost complete genome (5224 nt) of a novel bocavirus from feces of domestic minks, which has been provisionally named mink bocavirus. The NS1 protein of mink bocavirus shared 36.9-52 % amino acid sequence identities with those of other known bocaviruses and phylogenetically clustered with bocaviruses from other carnivores. According to the genetic distance-based criteria, mink bocavirus qualifies as a novel species of bocavirus. PCR of feces from a group of domestic minks, which included both healthy animals and animals suffering from diarrhea, revealed that 30 % (9/30) shed virus. However, no association between viral shedding and the presence of diarrhea could be determined.
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http://dx.doi.org/10.1007/s11262-016-1380-4DOI Listing
December 2016

MicroRNA-146b, a Sensitive Indicator of Mesenchymal Stem Cell Repair of Acute Renal Injury.

Stem Cells Transl Med 2016 10 8;5(10):1406-1415. Epub 2016 Jul 8.

Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China

: The role of mesenchymal stem cells (MSCs) in kidney injury repair has been studied widely. However, the underlying molecular mechanism remains unclear. We profiled the altered microRNAs in renal tissues from cisplatin-induced acute kidney injury (AKI) rats treated with or without rat bone marrow MSCs (rMSCs). We observed that microRNA-146b (miR-146b) expression was considerably upregulated in renal tissues from AKI rats compared with that in healthy rats, and the expression decreased following MSC treatment after cisplatin administration. At the early stage of AKI, serum miR-146b levels exhibited a rapid increase that was even faster than that of two conventional renal function indexes: serum creatinine and blood urea nitrogen levels. Furthermore, the serum miR-146b levels in AKI patients were higher than those in healthy people. In vitro exposure to cisplatin also increased miR-146b expression in renal tubular epithelial cells (TECs). miR-146b knockdown protected renal TECs from cisplatin-induced apoptosis and promoted their proliferation. Moreover, ErbB4 was identified as a direct target of miR-146b, and miR-146b inhibition induced ErbB4 expression, resulting in enhanced proliferation of injured renal TECs. In addition, restoration by rMSCs could be controlled through ErbB4 downregulation. In conclusion, elevated miR-146b expression contributes to cisplatin-induced AKI, partly through ErbB4 downregulation. miR-146b might be an early biomarker for AKI, and miR-146b inhibition could be a novel strategy for AKI treatment.

Significance: The present study found that microRNA-146b (miR-146b) might be a novel biomarker for acute kidney injury and an indicator for its recovery after treatment with mesenchymal stem cells (MSCs). The results showed that in acute kidney injury induced by cisplatin, miR-146b in serum increased more quickly than did the usual indexes of kidney injury and decreased with restoration of MSCs. In addition, inhibition of miR-146b could ameliorate the apoptosis induced by cisplatin and potentially improve the proliferation by freeing ErbB4 and its downstream proteins.
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http://dx.doi.org/10.5966/sctm.2015-0355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031179PMC
October 2016

Bufavirus Protoparvovirus in feces of wild rats in China.

Virus Genes 2016 Feb 24;52(1):130-3. Epub 2015 Nov 24.

Department of Laboratory Medicine, Blood Systems Research Institute, University of California San Francisco, San Francisco, CA, USA.

Bufavirus (BuV) was first discovered from feces of children with acute diarrhea. It was subsequently detected from several animal species including shrews, bats, and nonhuman primates. In this study, we identified a novel Protoparvovirus, designated RatBuV, from the intestinal contents of wild rats using viral metagenomics. The near complete genome was 4643 nt encoding NS1, VP1, and VP2 proteins. Phylogenetic analysis over the complete genome showed that RatBuV clustered with Mpulungu BuV from shrews. Sequence analysis indicated that the putative protein sequences of NS1, VP1, and VP2 of RatBuV shared identities of 50.6-77.2, 48.3-77.3, and 47.1-78.3 %, respectively, with those of human BuVs, MpBuV, and WUHARV parvovirus, suggesting RatBuV belongs to a new species of Protoparvovirus. Our epidemiologic study indicated that the prevalence rate of RatBuV in the cohort of 40 wild rats is 12.5 % (5/40), which is higher than that of BuV in humans in a previous study.
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http://dx.doi.org/10.1007/s11262-015-1262-1DOI Listing
February 2016

Tumorigenic hybrids between mesenchymal stem cells and gastric cancer cells enhanced cancer proliferation, migration and stemness.

BMC Cancer 2015 Oct 24;15:793. Epub 2015 Oct 24.

Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.

Background: Emerging evidence indicates that inappropriate cell-cell fusion might contribute to cancer progression. Similarly, mesenchymal stem cells (MSCs) can also fuse with other cells spontaneously and capable of adopting the phenotype of other cells. The aim of our study was to investigate the role of MSCs participated cell fusion in the tumorigenesis of gastric cancer.

Methods: We fused human umbilical cord mesenchymal stem cells (hucMSCs) with gastric cancer cells in vitro by polyethylene glycol (PEG), the hybrid cells were sorted by flow cytometer. The growth and migration of hybrids were assessed by cell counting, cell colony formation and transwell assays. The proteins and genes related to epithelial- mesenchymal transition and stemness were tested by western blot, immunocytochemistry and real-time RT-PCR. The expression of CD44 and CD133 was examined by immunocytochemistry and flow cytometry. The xenograft assay was used to evaluation the tumorigenesis of the hybrids.

Results: The obtained hybrids exhibited epithelial- mesenchymal transition (EMT) change with down-regulation of E-cadherin and up-regulation of Vimentin, N-cadherin, α-smooth muscle actin (α-SMA), and fibroblast activation protein (FAP). The hybrids also increased expression of stemness factors Oct4, Nanog, Sox2 and Lin28. The expression of CD44 and CD133 on hybrid cells was stronger than parental gastric cancer cells. Moreover, the migration and proliferation of heterotypic hybrids were enhanced. In addition, the heterotypic hybrids promoted the growth abilities of gastric xenograft tumor in vivo.

Conclusions: Taken together, our results suggest that cell fusion between hucMSCs and gastric cancer cells could contribute to tumorigenic hybrids with EMT and stem cell-like properties, which may provide a flexible tool for investigating the roles of MSCs in gastric cancer.
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http://dx.doi.org/10.1186/s12885-015-1780-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620013PMC
October 2015

Extracellular regulated protein kinases 1/2 phosphorylation is required for hepatic differentiation of human umbilical cord-derived mesenchymal stem cells.

Exp Biol Med (Maywood) 2015 Apr 8;240(4):534-45. Epub 2015 Jan 8.

Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China The Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China

Mesenchymal stem cells (MSCs) have the capacity to restore liver function by differentiating into hepatocyte like cells. However, the underlying mechanisms are not well understood. Here, we have investigated the signals involved in the hepatic differentiation of human umbilical cord-derived mesenchymal stem cells (hUCMSCs). hUCMSCs were treated with mouse fetal liver-conditioned medium (FLCM) to induce hepatic differentiation. Flow cytometry, reverse transcription PCR, real-time PCR, immunocytochemistry, and polymerase chain reaction (PCR) array were used to detect the expression of MSC- and hepotocyte-specific markers in FLCM-treated hUCMSCs. Urea production and cytochrome P450 3A4 (CYP3A4) activity were used as indicators to evaluate liver cell characteristics. Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) was analyzed in hUCMSCs by Western blotting. Following FLCM treatment, expression of MSC-specific markers decreased, while hepatocyte-specific gene expression was increased. Urea production, albumin secretion, glycogen storage, and CYP3A4 activity were significantly enhanced in FLCM-treated cells. In addition, ERK1/2 phosphorylation was increased in a time-dependent manner through Raf/MEK/ERK pathway, and phosphorylation was sustained at a high level during hepatic induction. Inhibition of ERK1/2 activation by U0126 (an ERK1/2 inhibitor) and pFLAG-CMV-ERK1(K71R) (negative mutant of ERK1) reversed the expression of liver-specific genes in hUCMSCs and affected hepatic function significantly. In summary, this work shows that ERK1/2 phosphorylation plays an important role in inducing hepatic differentiation of hUCMSCs in FLCM.
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http://dx.doi.org/10.1177/1535370214548996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935372PMC
April 2015

Gastric cancer-derived MSC-secreted PDGF-DD promotes gastric cancer progression.

J Cancer Res Clin Oncol 2014 Nov 18;140(11):1835-48. Epub 2014 Jun 18.

Centre for Clinical Laboratory of the Affiliated Hospital, Key Laboratory of Laboratory Medicine of Jiangsu Province, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212001, People's Republic of China.

Purpose: This study was designed to investigate the role of PDGF-DD secreted by gastric cancer-derived mesenchymal stem cells (GC-MSCs) in human gastric cancer progression.

Methods: Gastric cancer cells were indirectly co-cultured with GC-MSCs in a transwell system. The growth and migration of gastric cancer cells were evaluated by cell colony formation assay and transwell migration assay, respectively. The production of PDGF-DD in GC-MSCs was determined by using Luminex and ELISA. Neutralization of PDGFR-β by su16f and siRNA interference of PDGF-DD in GC-MSCs was used to demonstrate the role of PDGF-DD produced by GC-MSCs in gastric cancer progression.

Results: GC-MSC conditioned medium promoted gastric cancer cell proliferation and migration in vitro and in vivo. Co-culture with GC-MSCs increased the phosphorylation of PDGFR-β in SGC-7901 cells. Neutralization of PDGFR-β by su16f blocked the promoting role of GC-MSC conditioned medium in gastric cancer cell proliferation and migration. Recombinant PDGF-DD duplicated the effects of GC-MSC conditioned medium on gastric cancer cells. Knockdown of PDGF-DD in GC-MSCs abolished its effects on gastric cancer cells in vitro and in vivo.

Conclusions: PDGF-DD secreted by GC-MSCs is capable of promoting gastric cancer cell progression in vitro and in vivo. Targeting the PDGF-DD/PDGFR-β interaction between MSCs and gastric cancer cells may represent a novel strategy for gastric cancer therapy.
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http://dx.doi.org/10.1007/s00432-014-1723-2DOI Listing
November 2014

Macrophages are involved in the protective role of human umbilical cord-derived stromal cells in renal ischemia-reperfusion injury.

Stem Cell Res 2013 May 29;10(3):405-16. Epub 2013 Jan 29.

School of Medical Science and Laboratory Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China.

Administration of fibroblastic cells derived from a number of tissues (collectively called "mesenchymal stem cells") has been suggested to be beneficial for renal repair and mortality reduction in renal ischemia-reperfusion injury (IRI), but the underlying mechanism is not fully understood. In the present study, our objective was to investigate the involvement of macrophages in the therapeutic effect of human umbilical cord-derived stromal cells (hUCSCs) on renal IRI. Twenty-four hours after reperfusion, hUCSCs were injected intravenously and resulted in significant improvements in renal function, with a lower tubular injury score together with more proliferative and fewer apoptotic tubular cells in kidney tissue. Moreover, hUCSCs reduced the infiltration of macrophages into renal interstitium especially at 5 days post-reperfusion, while the proportion of anti-inflammatory M2 macrophages was markedly increased. HUCSCs also alleviated the local inflammatory response in kidneys. The absence of macrophages during the early phase of reperfusion enhanced the therapeutic effect of hUCSCs, whereas macrophage depletion during the late repair phase eliminated the renoprotective role of hUCSCs. In vitro, macrophages cocultured with hUCSCs were switched to the alternatively activated M2 phenotype. Our data indicate that hUCSCs are capable of promoting the M2 polarization of macrophages at injury sites, suggesting a new mechanism for hUCSC-mediated protection in renal IRI.
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http://dx.doi.org/10.1016/j.scr.2013.01.005DOI Listing
May 2013

Characterization of a coelomic gregarine parasite from Thitarodes pui (Lepidoptera: Hepialidae) in the Tibetan Plateau.

J Invertebr Pathol 2012 Oct 2;111(2):160-5. Epub 2012 Aug 2.

School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang 212013, China.

Thitarodes pui, one of the host species of entomopathogenic fungus Ophiocordyceps sinensis, has great economic importance in the Tibetan Plateau. We report here, for the first time, a gregarine parasite found in the coelom of 7th instar and adults of T. pui. Gregarine gamonts (ovoid, ~15×8 μm) underwent syzygy to produce reproductive gametocysts in T. pui larval hemolymph. All infected T. pui carried 2-17 mature gametocysts filled with numerous oocysts (lemon-shaped, 17.17±0.73×6.49±0.4 μm). Transmission electron microscopy showed that these oocysts contained vacuoles of various sizes and amylopectin granules in the cytoplasm; scanning electron microscopy revealed a number of small bumps all over the surface of these oocysts. Small subunit ribosomal DNA sequence analysis showed a close relationship between the gregarine and the species of Ascogregarina (Eugregarinorida: Lecudinidae). Internal transcribed spacers and 5.8S ribosomal DNA from this gregarine exhibited 76% highest sequence identity with that from Ascogregarina culicis Ross.
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http://dx.doi.org/10.1016/j.jip.2012.07.024DOI Listing
October 2012

Molecular characterization and gene expression of apolipophorin III from the ghost moth, Thitarodes pui (Lepidoptera, Hepialidae).

Arch Insect Biochem Physiol 2012 Jun 29;80(1):1-14. Epub 2011 Nov 29.

State Key Laboratory for Biological Control/Institute of Entomology, Sun Yat-Sen University, Guangzhou, People' Republic of China.

Apolipophorin III (apoLp-III) functions in lipid transport and immune activation in insects. We cloned a cDNA encoding putative apoLp-III from larvae of Thitarodes pui, a host species of Ophiocordyceps sinensis, with great economic importance in the Tibetan Plateau. Excluding a putative signal peptide of the first 20 amino acid residues, the 171-residue mature apoLp-III has a calculated molecular mass of 18,606 Da. T. pui apoLp-III shares little sequence homologies (<36%) with other apoLp-IIIs. Phylogenetic analysis reveals that T. pui apoLp-III belongs to a distinct, early diverging lineage of lepidopteran apoLp-IIIs. Homology modeling of T. pui apoLp-III shows a bundle of five amphipathic α-helices, including a short helix 3'. T. pui apoLp-III was constitutively expressed in larval fat body at lower levels than pupal and adult fat body. Significant induction of apoLp-III expression, associated with strongest nodulation response, was observed in both sixth and eighth instar larvae challenged with Beauveria bassiana conidia at 1 hr after inoculation, compared with saline-injected controls. The inoculation experiment as well as previous field studies revealed the relative susceptibility of the sixth instar to the entomopathogenic fungus. ApoLp-III transcripts in the infected sixth and eighth instars were found to be induced highest 2- and 14.7-fold, respectively, during the first 12 hr. In late-stage infection, the infected susceptible sixth instar showed decrease in apoLp-III expression followed by production of B. bassiana hyphal bodies, whereas the infected eighth instar showed longer lasting increase in the expression. These results suggest that apoLp-III might contribute to T. pui immune response against fungal pathogens.
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http://dx.doi.org/10.1002/arch.20456DOI Listing
June 2012

Structure and expression of β-1,3-glucan recognition proteins from the ghost moth, Thitarodes pui (Hepialidae), and their response to Beauveria bassiana infection.

J Insect Physiol 2011 Dec 3;57(12):1660-9. Epub 2011 Sep 3.

State Key Laboratory for Biological Control/Institute of Entomology, Sun Yat-sen University, Guangzhou 510275, China.

Beta-1,3-glucan recognition proteins (βGRPs), as a class of pattern recognition receptors, are involved in activation of the immune response in invertebrates. We cloned two cDNAs encoding putative βGRPs from larvae of Thitarodes pui, a host species of Ophiocordyceps sinensis with great economic importance in the Tibetan Plateau. The two putative βGRPs were phylogenetically classified into a novel clade 4, and designated TpβGRP-4a and TpβGRP-4b, respectively, with calculated molecular masses of 53,265 and 43,991 Da. Both TpβGRPs contained a C-terminal domain with sequence similarity to β-1,3-glucanases but without the glucanase active site. TpβGRP-4b markedly differed from other family members including TpβGRP-4a in the N-terminal region by a large deletion of ∼80 amino acid residues. Homology modelings revealed an eight-stranded β-sandwich fold (β1-β8) and two β-strands (only β1 and β2), respectively, in the N-terminal domains of TpβGRP-4a and -4b. TpβGRPs showed similar developmental expression patterns in fat body. TpβGRP-4a and -4b transcripts were induced highest 313- and 16-fold, respectively, in resistant 8th instar larvae challenged with conidia of entomopathogenic fungus Beauveria bassiana. By contrast, significant reductions in TpβGRPs expression were observed in conidia-injected susceptible 6th instar larvae (compared with saline-injected controls), accompanied by production of hyphal bodies in hemolymph. These results suggest that TpβGRPs might contribute to host defense against fungal infection, and TpβGRP-4b with the unusual deletion of the N-terminal region might have evolved new functions for βGRP family proteins.
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http://dx.doi.org/10.1016/j.jinsphys.2011.08.019DOI Listing
December 2011

Molecular cloning and characterization of two heat shock proteins in Thitarodes pui (Lepidoptera: Hepialidae).

Cryo Letters 2011 May-Jun;32(3):225-39

State Key Laboratory for Biological Control, Sun Yat-sen University, Guangzhou, China.

Heat shock proteins (HSPs) show transient expression in response to rapid temperature increase. The larvae of Thitarodes insects are the host of Ophiocordyceps sinensis, with high cold-tolerance. In order to study the adaptive mechanisms to temperature change, we cloned and sequenced the full-length cDNAs of two HSP genes (designated as tp-hsp90 and tp-hsp70) using the technique of rapid amplification of cDNA ends (RACE) from T. pui. The complete cDNA sequences of tp-hsp90 and tp-hsp70 are 2,842 bp and 2,169 bp long, encoding polypeptides of 712 and 651 amino acids with molecular weights of 81.57 and 71.27 kDa respectively. They show significant sequence similarity to homologous genes in insects. The inferred amino acid sequences of tp-hsp90 and tp-hsp70 are characterized by conserved features of HSP family: the proteins contain five signature sequences of HSP90 and three signatures of HSP70, respectively. Real-time quantitative reverse transcription-PCR (qRT-PCR) analyses show that tp-hsp90 expression is up-regulated in October and December, followed by a gradual rebound in January, March and May; while tp-hsp70 expression does not change significantly during the same period. These results suggest that tp-hsp90, rather than tp-hsp70, responds to temperature changes and should play a key role in cold tolerance in Thitarodes pui.
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September 2011