Publications by authors named "Yaoxiang Sun"

8 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

3,3'-Diindolylmethane Promotes Gastric Cancer Progression β-TrCP-Mediated NF-κB Activation in Gastric Cancer-Derived MSCs.

Front Oncol 2021 24;11:603533. Epub 2021 Mar 24.

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

Gastric cancer is a malignant tumor characterized by high morbidity and invasion. Surgery combined with chemo-radiotherapy is the most common treatment for gastric cancer, while multiple drug resistance always results in treatment failure. Once the anti-tumor drugs enter the tumor foci, tumor cells as well as those found in the microenvironment are affected. However, the effects of drugs on tumor microenvironment (TME) are easily overlooked. In this study, we investigated the effects of the anti-cancer drug 3,3'-diindolylmethane (DIM) on gastric cancer-derived mesenchymal stem cells (GC-MSCs) and their subsequent impact on cancer progression. Surprisingly, we found that the therapeutic concentration of DIM upregulated the expression level of tumor-related factors such as CCL-2, IL-6, and IL-8 in GC-MSCs. The conditioned medium of DIM-treated GC-MSCs promoted the proliferation, invasion, and migration of gastric cancer cells and tumor growth . Mechanistically, DIM enhanced the expression of β-TrCP, an E3 ubiquitin ligase leading to IκBα degradation and NF-κB activation in GC-MSCs. The β-TrCP knockdown partially eliminated positive results caused by DIM. Our results showed that the therapeutic dosage of DIM induced cell death in cancer cells, while enhancing MSC paracrine functions in the stroma to offset the original DIM effect on cancer cells. These findings provide a new mechanism of anti-cancer drug resistance and remind us to adjust the chemotherapeutic scheme by combining the anti-cancer drug with an appropriate signaling pathway inhibitor to block the side effects of drug on targeted TME cells.
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http://dx.doi.org/10.3389/fonc.2021.603533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024625PMC
March 2021

Resveratrol improves human umbilical cord-derived mesenchymal stem cells repair for cisplatin-induced acute kidney injury.

Cell Death Dis 2018 09 20;9(10):965. Epub 2018 Sep 20.

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, Jiangsu, People's Republic of China.

Human umbilical cord-derived mesenchymal stem cells (hucMSCs) are a promising tool for damaged tissues repair, especially for the kidney. However, their efficacy requires improvement. In order to optimize the clinical utility of hucMSCs, we adopted a strategy of treating hucMSCs with 20 μmol/L of resveratrol (Res-hucMSCs), applying it in a cisplatin-induced acute kidney injury model. Interestingly, we found that Res-hucMSCs exhibited a more efficient repairing effect than did hucMSCs. Resveratrol-promoted hucMSCs secreted platelet-derived growth factor-DD (PDGF-DD) into renal tubular cells resulting in downstream phosphorylation of extracellular signal-regulated kinase (ERK), which inhibited renal tubular cells apoptosis. In contrast, PDGF-DD knockdown impaired the renal protection of Res-hucMSCs. In addition, angiogenesis induced by PDGF-DD in endothelial cells was also involved in the renal protection of Res-hucMSCs. The conditioned medium of Res-hucMSCs accelerated proliferation and migration of vascular endothelial cells in vitro and CD31 was in a high-level expression in Res-hucMSCs group in vivo. Nevertheless, the angiogenesis was abrogated when Res-hucMSCs were treated with PDGF-DD siRNA. In conclusion, our findings showed that resveratrol-modified hucMSCs activated ERK pathway in renal tubular cells and promoted angiogenesis in endothelial cells via paracrine PDGF-DD, which could be a novel strategy for enhancing the therapy efficacy of hucMSCs in cisplatin-induced kidney injury.
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http://dx.doi.org/10.1038/s41419-018-0959-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148224PMC
September 2018

Human Mesenchymal Stem Cell Derived Exosomes Alleviate Type 2 Diabetes Mellitus by Reversing Peripheral Insulin Resistance and Relieving β-Cell Destruction.

ACS Nano 2018 08 7;12(8):7613-7628. Epub 2018 Aug 7.

Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China.

Exosomes are nanosized extracellular vesicles (EVs) that show great promise in tissue regeneration and injury repair as mesenchymal stem cell (MSC). MSC has been shown to alleviate diabetes mellitus (DM) in both animal models and clinical trials. In this study, we aimed to investigate whether exosomes from human umbilical cord MSC (hucMSC-ex) have a therapeutic effect on type 2 DM (T2DM). We established a rat model of T2DM using a high-fat diet and streptozotocin (STZ). We found that the intravenous injection of hucMSC-ex reduced blood glucose levels as a main paracrine approach of MSC. HucMSC-ex partially reversed insulin resistance in T2DM indirectly to accelerate glucose metabolism. HucMSC-ex restored the phosphorylation (tyrosine site) of the insulin receptor substrate 1 and protein kinase B in T2DM, promoted expression and membrane translocation of glucose transporter 4 in muscle, and increased storage of glycogen in the liver to maintain glucose homeostasis. HucMSC-ex inhibited STZ-induced β-cell apoptosis to restore the insulin-secreting function of T2DM. Taken together, exosomes from hucMSC can alleviate T2DM by reversing peripheral insulin resistance and relieving β-cell destruction, providing an alternative approach for T2DM treatment.
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http://dx.doi.org/10.1021/acsnano.7b07643DOI Listing
August 2018

3,3'-Diindolylmethane stimulates exosomal Wnt11 autocrine signaling in human umbilical cord mesenchymal stem cells to enhance wound healing.

Theranostics 2017 10;7(6):1674-1688. Epub 2017 Apr 10.

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

Human umbilical cord-derived mesenchymal stem cells (hucMSCs) are suggested as a promising therapeutic tool in regenerative medicine, however, their efficacy requires improvement. Small molecules and drugs come up to be a convenient strategy in regulating stem cells fate and function. Here, we evaluated 3,3'-diindolylmethane (DIM), a natural small-molecule compound involved in the repairing effects of hucMSCs on a deep second-degree burn injury rat model. HucMSCs primed with 50 μM of DIM exhibited desirable repairing effects compared with untreated hucMSCs. DIM enhanced the stemness of hucMSCs, which was related to the activation of Wnt/β-catenin signaling. β-catenin inhibition impaired the healing effects of DIM-primed hucMSCs (DIM-hucMSCs) . Moreover, we demonstrated that DIM upregulated Wnt11 expression in hucMSC-derived exosomes. Wnt11 knockdown inhibited β-catenin activation and stemness induction in DIM-hucMSCs and abrogated their therapeutic effects . Thus, our findings indicate that DIM promotes the stemness of hucMSCs through increased exosomal Wnt11 autocrine signaling, which provides a novel strategy for improving the therapeutic effects of hucMSCs on wound healing.
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http://dx.doi.org/10.7150/thno.18082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436520PMC
February 2018

Exosomes derived from gastric cancer cells activate NF-κB pathway in macrophages to promote cancer progression.

Tumour Biol 2016 Sep 25;37(9):12169-12180. Epub 2016 May 25.

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

Exosomes are nano-sized membrane vesicles secreted by both normal and cancer cells. Emerging evidence indicates that cancer cells derived exosomes contribute to cancer progression through the modulation of tumor microenvironment. However, the effects of exosomes derived from gastric cancer cells on macrophages are not well understood. In this study, we investigated the biological role of gastric cancer cells derived exosomes in the activation of macrophages. We demonstrated that gastric cancer cells derived exosomes activated macrophages to express increased levels of proinflammatory factors, which in turn promoted tumor cell proliferation and migration. In addition, gastric cancer cells derived exosomes remarkably upregulated the phosphorylation of NF-κB in macrophages. Inhibiting the activation of NF-κB reversed the upregulation of proinflammatory factors in macrophages and blocked their promoting effects on gastric cancer cells. Moreover, we found that gastric cancer cells derived exosomes could also activate macrophages from human peripheral blood monocytes through the activation of NF-κB. In conclusion, our results suggest that gastric cancer cells derived exosomes stimulate the activation of NF-κB pathway in macrophages to promote cancer progression, which provides a potential therapeutic approach for gastric cancer by interfering with the interaction between exosomes and macrophages in tumor microenvironment.
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http://dx.doi.org/10.1007/s13277-016-5071-5DOI Listing
September 2016

Anti-cancer drug 3,3'-diindolylmethane activates Wnt4 signaling to enhance gastric cancer cell stemness and tumorigenesis.

Oncotarget 2016 Mar;7(13):16311-24

Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.

As a natural health supplement, 3,3'-diindolylmethane (DIM) is proposed as a preventive and chemotherapeutic agent for cancer by inhibiting cell proliferation and inducing cell apoptosis. However, we found that in contrary to high level of DIM (30 μM), low level of DIM (1 μM and 10 μM) obviously promoted gastric cancer cell growth and migration. In addition, we found that low level of DIM increased the expression of stemness factors and enhanced the pluripotency of gastric cancer cells. Low level of DIM promoted gastric cancer progression by inducing the PORCN-dependent secretion of Wnt4 and the activation of β-catenin signaling. Wnt4 knockdown reversed the effects of low level of DIM on gastric cancer cells. The results of in vivo studies showed that gastric cancer cells treated with low level of DIM (1 μM) grew faster and expressed higher level of Wnt4 than control cells. Taken together, our findings indicate that low level of DIM activates autocrine Wnt4 signaling to enhance the progression of gastric cancer, which may suggest an adverse aspect of DIM in cancer therapy. Our findings will provide a new aspect for the safety of DIM in its clinical application.
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http://dx.doi.org/10.18632/oncotarget.7684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941316PMC
March 2016

Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/β-catenin pathway.

Stem Cells Transl Med 2015 May 30;4(5):513-22. Epub 2015 Mar 30.

Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, Jiangsu University, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China; Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu, People's Republic of China

Human umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes have been considered as potential therapeutic tools for tissue regeneration; however, the underlying mechanisms are still not well understood. In this study, we isolated and characterized the exosomes from hucMSCs (hucMSC-Ex) and demonstrated that hucMSC-Ex promoted the proliferation, migration, and tube formation of endothelial cells in a dose-dependent manner. Furthermore, we demonstrated that hucMSC-Ex promoted wound healing and angiogenesis in vivo by using a rat skin burn model. We discovered that hucMSC-Ex promoted β-catenin nuclear translocation and induced the increased expression of proliferating cell nuclear antigen, cyclin D3, N-cadherin, and β-catenin and the decreased expression of E-cadherin. The activation of Wnt/β-catenin is critical in the induction of angiogenesis by hucMSC-Ex, which could be reversed by β-catenin inhibitor ICG-001. Wnt4 was delivered by hucMSC-Ex, and the knockdown of Wnt4 in hucMSC-Ex abrogated β-catenin nuclear translocation in endothelial cells. The in vivo proangiogenic effects were also inhibited by interference of Wnt4 expression in hucMSC-Ex. Taken together, these results suggest that hucMSC-Ex-mediated Wnt4 induces β-catenin activation in endothelial cells and exerts proangiogenic effects, which could be an important mechanism for cutaneous wound healing.
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http://dx.doi.org/10.5966/sctm.2014-0267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414225PMC
May 2015