Publications by authors named "Xiufen Zheng"

82 Publications

TdIF1-LSD1 Axis Regulates Epithelial-Mesenchymal Transition and Metastasis via Histone Demethylation of E-Cadherin Promoter in Lung Cancer.

Int J Mol Sci 2021 12 27;23(1). Epub 2021 Dec 27.

Institute of Immunotherapy, College of Basic Medicine, The First Affiliated Hospital of Nanchang University, Jiangxi Academy of Medical Sciences, Nanchang 330046, China.

We have previously found that TdT-interacting factor 1 (TdIF1) is a potential oncogene expressed in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. However, its exact mechanism is still unclear. The lysine-specific demethylase 1 (LSD1) is a crucial mediator of the epithelial-mesenchymal transition (EMT), an important process triggered during cancer metastasis. Here, we confirm that TdIF1 is highly expressed in NSCLC and related to lymph node metastasis through The Cancer Genome Atlas (TCGA) analysis of clinical samples. Silencing TdIF1 can regulate the expression of EMT-related factors and impair the migration and invasion ability of cancer cells in vitro. An analysis of tumor xenografts in nude mice confirmed that silencing TdIF1 inhibits tumor growth. Furthermore, we determined the interaction between TdIF1 and LSD1 using immunoprecipitation. Chromatin immunoprecipitation (ChIP) revealed that TdIF1 was enriched in the E-cadherin promoter region. The knockdown of TdIF1 repressed the enrichment of LSD1 at the E-cadherin promoter region, thereby regulating the level of promoter histone methylation and modulating E-cadherin transcription activity, ultimately leading to changes in EMT factors and cancer cell migration and invasion ability. The LSD1 inhibitor and TdIF1 knockdown combination showed a synergistic effect in inhibiting the growth, migration, and invasion of NSCLC cells. Taken together, this is the first demonstration that TdIF1 regulates E-cadherin transcription by recruiting LSD1 to the promoter region, thereby promoting EMT and tumor metastasis and highlighting the potential of TdIF1 as a therapeutic target for NSCLC.
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http://dx.doi.org/10.3390/ijms23010250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745707PMC
December 2021

Anti-Fibrotic Effects of Low Toxic Microcystin-RR on Bleomycin-Induced Pulmonary Fibrosis: A Comparison with Microcystin-LR.

Front Pharmacol 2021 8;12:675907. Epub 2021 Jun 8.

Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pulmonary disease characterized with radiographically evident pulmonary infiltrates and extracellular matrix deposition with limited treatment options. We previously described that microcystin-LR (MC-LR) reduces transforming growth factor (TGF)-β1/Smad signaling and ameliorates pulmonary fibrosis in bleomycin (BLM)-induced rat models. In the present study, we further demonstrate that microcystin-RR (MC-RR), an MC congener with lower toxicity than MC-LR, exerted an anti-fibrotic effect on BLM-induced pulmonary fibrosis rodent models and compared it with MC-LR. Our data show that MC-RR treatment attenuated BLM-associated pulmonary inflammation and collagen deposition in both therapeutic and preventive models. MC-RR reduced the expression of fibrotic markers, including vimentin, α-smooth muscle actin, collagen 1α1, and fibronectin, in rat pulmonary tissues. Furthermore, the core features of BLM-induced pulmonary fibrotic lesions were better alleviated by MC-RR than by MC-LR. MC-RR treatment substantially decreased the number of pulmonary M2 macrophages. , MC-RR attenuated the epithelial-mesenchymal transition and fibroblast-myofibroblast transition triggered by M2 macrophages. Therefore, we highlight MC-RR as a promising molecule for developing therapeutic and prophylactic strategies against IPF, a refractory lung disease.
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http://dx.doi.org/10.3389/fphar.2021.675907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217630PMC
June 2021

Preventing alloimmune rejection using circular RNA FSCN1-silenced dendritic cells in heart transplantation.

J Heart Lung Transplant 2021 07 8;40(7):584-594. Epub 2021 Apr 8.

Department of Pathology and Laboratory Medicine, Western University, London, Ontario Canada; Department of Surgery, Western University, London, Ontario Canada; Lawson Health Research Institute, London, Ontario Canada; Department of Oncology, Western University, London, Ontario Canada. Electronic address:

Background: While heart transplantation is used as a standard treatment for heart failure, transplant rejection continues to pose a challenge. Recent evidence has shown that circular RNA (circRNA) is a new type of gene regulator in cell development. Our aim was to demonstrate that treatment with tolerogenic dendritic cells (Tol-DCs) generated by circular RNA FSCN1 (circFSCN1) silencing could prevent alloimmune rejection and prolong heart graft survival in heart transplantation.

Methods: Bone marrow-derived DCs were transfected with circFSCN1 siRNA in vitro. The circFSCN1 level was measured by qRT-PCR. DC maturation was determined by flow cytometry. Mixed lymphocyte reactions (MLRs) were conducted to assess the function of DCs to activate T cells and to generate regulatory T cells (Tregs). In situ RNA hybridization and fluorescent microscopy were performed to detect the distribution of circFSCN1 in DCs. A heterotopic allogeneic murine heart transplantation was conducted where recipients were pre-treated with donor derived circFSCN1-silenced Tol-DCs. Heartbeat was monitored to assess immune rejection.

Results: Exonic circFSCN1 was highly expressed in the cytoplasm of mature DCs. Knockdown of circFSCN1 using siRNA arrested DCs at an immature state, impaired DC's ability to activate T cells and enhanced Treg generation. Treatment with circFSCN1-silenced Tol-DCs prevented alloimmune rejection, prolonged allograft survival, reduced fibrosis, and induced Tregs in vivo.

Conclusions: Knockdown of circFSCN1 induces Tol-DCs and treatment with these Tol-DCs prevents alloimmune rejection and prolongs allograft survival. This is a promising therapeutic target to combat transplant rejection in heart transplantation and increases our understanding of circRNA in the immune system.
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http://dx.doi.org/10.1016/j.healun.2021.03.025DOI Listing
July 2021

Circular RNA in colorectal cancer.

J Cell Mol Med 2021 04 9;25(8):3667-3679. Epub 2021 Mar 9.

Department of Pathology and Laboratory Medicine, Western University, London, Canada.

Circular RNA (circRNA) is a highly abundant type of single-stranded non-coding RNA. Novel research has discovered many roles of circRNA in colorectal cancer (CRC) including proliferation, metastasis and apoptosis. Furthermore, circRNAs also play a role in the development of drug resistance and have unique associations with tumour size, staging and overall survival in CRC that lend circRNAs the potential to serve as diagnostic and prognostic biomarkers. Among cancers worldwide, CRC ranks second in mortality and third in incidence. In order to have a better understanding of the influence of circRNA on CRC development and progression, this review summarizes the role of specific circRNAs in CRC and evaluates their potential value as therapeutic targets and biomarkers for CRC. We aim to provide insight in the development of therapy and clinical decision-making.
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http://dx.doi.org/10.1111/jcmm.16380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051750PMC
April 2021

FAM83H-AS1 is a noncoding oncogenic driver and therapeutic target of lung adenocarcinoma.

Clin Transl Med 2021 02;11(2):e316

Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China.

Background: Little is known about noncoding oncogenes of lung adenocarcinoma (LUAD), and these potential drivers might provide novel therapeutic targets.

Methods: Since abnormally overexpression of oncogenic drivers is induced by genomic variation, we here utilized genomic, transcriptomic, and clinical prognosis data of The Cancer Genome Atlas (TCGA) LUAD datasets to discover novel drivers from long noncoding RNAs. We further used zebrafish models to validate the biological function of candidates in vivo. The full length of FAM83H-AS1 was obtained by rapid amplification of the cDNA ends assay. RNA pull-down, RNA immunoprecipitation, quantitative mass spectrometry, and RNA sequencing assays were conducted to explore the potential mechanisms. Additionally, we used CRISPR interference (CRISPRi) method and patient-derived tumor xenograft (PDTX) model to evaluate the therapeutic potential of targeting FAM83H-AS1.

Results: The results suggest that FAM83H-AS1 is a potential oncogenic driver due to chromosome 8q24 amplification. Upregulation of FAM83H-AS1 results in poor prognosis of LUAD patients in both Jiangsu Cancer Hospital (JSCH) and TCGA cohorts. Functional assays revealed that FAM83H-AS1 promotes malignant progression and inhibits apoptosis. Mechanistically, FAM83H-AS1 binds HNRNPK to enhance the translation of antiapoptotic oncogenes RAB8B and RAB14. Experiments using CRISPRi-mediated xenografts and PDTX models indicated that targeting FAM83H-AS1 inhibited LUAD progression in vivo.

Conclusions: Our work demonstrates that FAM83H-AS1 is a noncoding oncogenic driver that inhibits LUAD apoptosis via the FAM83H-AS1-HNRNPK-RAB8B/RAB14 axis, which highlights the importance and potential roles that FAM83H-AS1 may serve as a novel therapeutic target for LUAD.
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http://dx.doi.org/10.1002/ctm2.316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882096PMC
February 2021

Circular RNA Foxo3 in cardiac ischemia-reperfusion injury in heart transplantation: A new regulator and target.

Am J Transplant 2021 09 2;21(9):2992-3004. Epub 2021 Feb 2.

Department of Pathology, Western University, London, Ontario, Canada.

Ischemia-reperfusion (I/R) injury occurring in heart transplantation (HT) remains as a leading cause of transplant heart graft failure. Circular RNAs (circRNAs) play important roles in gene regulation and diseases. However, the impact of circRNAs on I/R injury during HT remains unknown. This study aims to investigate the role of circular RNA Foxo3 (circFoxo3) in I/R injury in HT. Using an in vivo mouse HT model and an in vitro cardiomyocyte culture model, we demonstrated that circFoxo3 is significantly upregulated in I/R-injured hearts and hypoxia/reoxygenation (H/R)-damaged cardiomyocytes. Knockdown of circFoxo3 using siRNA not only reduces cell apoptosis and death, mitochondrial damage, and expression of apoptosis/death-related genes in vitro, but also protects heart grafts from prolonged cold I/R injury in HT. We also show that circFoxo3 interacts with Foxo3 proteins and inhibits the phosphorylation of Foxo3 and that it indirectly affects the expression of miR-433 and miR-136. In conclusion, circRNA is involved in I/R injury in HT and knockdown of circFoxo3 with siRNA can reduce I/R injury and improve heart graft function through interaction with Foxo3. This study highlights that circRNA is a new type of molecular regulator and a potential target for preventing I/R injury in HT.
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http://dx.doi.org/10.1111/ajt.16475DOI Listing
September 2021

An Addition of U0126 Protecting Heart Grafts From Prolonged Cold Ischemia-Reperfusion Injury in Heart Transplantation: A New Preservation Strategy.

Transplantation 2021 02;105(2):308-317

Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Background: Ischemia-reperfusion injury (IRI) is the major cause of primary graft dysfunction in organ transplantation. The mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) signaling pathway plays a crucial role in cell physiological and pathological processes including IRI. This study aims to investigate whether inhibition of ERK signaling with U0126 can prevent prolonged cold IRI in heart transplantation.

Methods: Rat cardiac cell line H9c2 cells were treated with U0126 before exposure to hypothermic hypoxia/reoxygenation (H/R) conditions. The effect of U0126 on H9c2 cells in response to H/R stress was determined by measuring cell death, reactive oxygen species production, mitochondrial membrane potential, and ERK signaling activation. Mouse syngeneic heterotopic heart transplantation was conducted, where a donor heart was preserved in the University of Wisconsin (UW) solution supplemented with U0126 for 24 hours at 4°C before transplantation. Heart graft function, histopathologic changes, apoptosis, and fibrosis were measured to assess IRI.

Results: Phosphorylated ERK was increased in both in vitro H/R-injured H9c2 cells and in vivo heart grafts with IRI. Pretreatment with U0126 inhibited ERK phosphorylation and prevented H9c2 cells from cell death, reactive oxygen species generation, and mitochondrial membrane potential loss in response to H/R. Preservation of donor hearts with U0126-supplemented solution improved graft function and reduced IRI by reductions in cell apoptosis/death, neutrophil infiltration, and fibrosis of the graft.

Conclusions: Addition of U0126 to UW solution reduces ERK signal activation and attenuates prolonged cold IRI in a heart transplantation model. ERK inhibition with U0126 may be a useful strategy to minimize IRI in organ transplantation.
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http://dx.doi.org/10.1097/TP.0000000000003402DOI Listing
February 2021

The role of miR-711 in cardiac cells in response to oxidative stress and its biogenesis: a study on H9C2 cells.

Cell Mol Biol Lett 2020 9;25:26. Epub 2020 Apr 9.

2Department of Pathology and Laboratory Medicine, Western University, London, Ontario Canada.

Background: Oxidative stress results in cell apoptosis/death and plays a detrimental role in disease development and progression. Stressors alter the miRNA expression profile and miRNAs play a role in the cell response to stress. We previously showed that miR-711 is significantly over-expressed in extended cold ischemia reperfusion injured hearts in heart transplant. In this study, we aimed to investigate the role of miR-711 in cardiac cell damage in response to oxidative stress and how miR-711 is regulated.

Methods: Rat cardiac cell line H9c2 cells were cultured and exposed to oxidative conditions (Antimycin A (AA), HO, CoCl, or cold hypoxia/reoxygenation (H/R)) in vitro. H9c2 cells were transfected with miR-711 mimics, miR-711 inhibitors, or small interference RNA, using transfection reagents. The expression of miR-711 was measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Cell apoptosis/death was detected by flow cytometry and an IncuCyte system. Mitochondrial damage was detected by measuring the mitochondria membrane potential by flow cytometry. Gene expression was detected by qRT-PCR at the mRNA level and Western blotting and immunocytochemistry staining at the protein level.

Results: We found that miR-711 was significantly up-regulated in cells treated with HO, AA, CoCl, and cold H/R. Over-expression of miR-711 increased cell apoptosis/death induced by AA and H/R whereas cell death was reduced by miR-711 inhibitors. MiR-711 induced cell death through negative regulation of angiopoietin 1 (Ang-1), fibroblast growth factor 14 (FGF14) and calcium voltage-gated channel subunit alpha1C (Cacna1c) genes. Both knockdown of hypoxia inducible factor 1α (HIF-1α) and inactivation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NFКB) pathway inhibited over-expression of miR-711.

Conclusion: Oxidative stress increases the expression of miR-711. Over-expression of miR-711 induces cell apoptosis/death. HIF-1α and NFКB regulate miR-711 in H9c2 cells during oxidative stress. miR-711 is a new target for preventing oxidative stress.
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http://dx.doi.org/10.1186/s11658-020-00206-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146913PMC
December 2020

The long non-coding RNA PIK3CD-AS2 promotes lung adenocarcinoma progression via YBX1-mediated suppression of p53 pathway.

Oncogenesis 2020 Mar 12;9(3):34. Epub 2020 Mar 12.

Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.

The underlying mechanisms of long non-coding RNAs (lncRNA) participating in the progression of lung cancers are largely unknown. We found a novel lncRNA, PIK3CD antisense RNA 2 (PIK3CD-AS2), that contributes to lung adenocarcinoma (LUAD) progression. The expression characteristics of PIK3CD-AS2 in LUAD were analyzed using microarray expression profile, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, and validated in 92 paired LUAD tissues by chromogenic in situ hybridization. Our data confirmed that PIK3CD-AS2 expression is a crucial regulator of LUAD progression and associated with shorter patient survival. In vitro studies showed that PIK3CD-AS2 increased cell growth and slowed apoptosis in p53 cells but not in p53 cells. Mechanically, it is demonstrated that PIK3CD-AS2 bound to and maintained the stability of Y-box binding protein 1 (YBX1), a potent destabilizer of p53, by impeding its ubiquitination and degradation. Downexpression of YBX1 reversed PIK3CD-AS2-mediated inhibition of p53 signaling. Additionally, the therapeutic effect evaluation of a locked nuclear acid (LNA) specifically targeting PIK3CD-AS2 showed an anti-tumor activity in mice with A549 cells xenograft and p53 wild-type LUAD patient-derived tumor xenograft (PDTX) model. Clinically, the high expression of PIK3CD-AS2 showed a poor disease-free survival in p53 wild-type patients in TCGA database. Our findings suggest that PIK3CD-AS2 regulates LUAD progression and elucidate a new PIK3CD-AS2/YBX1/p53 signaling axis, providing a potential lncRNA-directed therapeutic strategy especially in p53 wild-type LUAD patients.
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http://dx.doi.org/10.1038/s41389-020-0217-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067885PMC
March 2020

Microcystin-LR ameliorates pulmonary fibrosis via modulating CD206 M2-like macrophage polarization.

Cell Death Dis 2020 02 19;11(2):136. Epub 2020 Feb 19.

Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, 210093, China.

Idiopathic pulmonary fibrosis (IPF) is a group of chronic interstitial pulmonary diseases characterized by myofibroblast proliferation and extracellular matrix deposition with limited treatment options. Based on our previous observation, we hypothesized microcystin-leucine arginine (LR), an environmental cyanobacterial toxin, could potentially suppress pulmonary fibrosis. In this study, we first demonstrated that chronic exposure of microcystin-LR by oral for weeks indeed attenuated the pulmonary fibrosis both on bleomycin-induced rat and fluorescein isothiocyanate-induced mouse models. Our data further indicated that treatment with microcystin-LR substantially reduced TGF-β1/Smad signaling in rat pulmonary tissues. The experiments in vitro found that microcystin-LR was capable of blocking epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transition (FMT) through suppressing the differentiation of CD206 macrophages. Mechanically, microcystin-LR was found to bind to glucose-regulated protein 78 kDa (GRP78) and suppress endoplasmic reticulum unfolded protein response (UPR) signaling pathways. These events led to the modulation of M2 polarization of macrophages, which eventually contributed to the alleviation of pulmonary fibrosis. Our results revealed a novel mechanism that may account for therapeutic effect of microcystin-LR on IPF.
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http://dx.doi.org/10.1038/s41419-020-2329-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031231PMC
February 2020

Squid Ink Polysaccharides Protect Human Fibroblast Against Oxidative Stress by Regulating NADPH Oxidase and Connexin43.

Front Pharmacol 2019 17;10:1574. Epub 2020 Jan 17.

Department of Dermatology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, China.

Oxidation injury to skin is one of the main reasons for skin aging. The aim of the present study was to explore the protective effect of squid ink polysaccharides and its mechanism of action against HO-induced dermal fibroblast damage. Our results show that squid ink polysaccharides effectively reduce the fibroblast oxidative damage mediated by the up-regulation of NADPH oxidase and Connexin43. Concurrently, squid ink polysaccharides decrease the ROS induced up-regulation of MMP1 and MMP9 to decrease MMP-mediated skin aging. Therefore, we hypothesize that squid ink polysaccharides play an antioxidant role by inhibiting the expression of NADPH oxidase and connexin43. This provides a new target for the effective clinical prevention and treatment of oxidative skin damage.
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http://dx.doi.org/10.3389/fphar.2019.01574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978904PMC
January 2020

CD5 blockade enhances ex vivo CD8 T cell activation and tumour cell cytotoxicity.

Eur J Immunol 2020 05 25;50(5):695-704. Epub 2020 Feb 25.

Department of Microbiology and Immunology, Western University, London, Ontario, Canada.

CD5 is expressed on T cells and a subset of B cells (B1a). It can attenuate TCR signalling and impair CTL activation and is a therapeutic targetable tumour antigen expressed on leukemic T and B cells. However, the potential therapeutic effect of functionally blocking CD5 to increase T cell anti-tumour activity against tumours (including solid tumours) has not been explored. CD5 knockout mice show increased anti-tumour immunity: reducing CD5 on CTLs may be therapeutically beneficial to enhance the anti-tumour response. Here, we show that ex vivo administration of a function-blocking anti-CD5 MAb to primary mouse CTLs of both tumour-naïve mice and mice bearing murine 4T1 breast tumour homografts enhanced their capacity to respond to activation by treatment with anti-CD3/anti-CD28 MAbs or 4T1 tumour cell lysates. Furthermore, it enhanced TCR signalling (ERK activation) and increased markers of T cell activation, including proliferation, CD69 levels, IFN-γ production, apoptosis and Fas receptor and Fas ligand levels. Finally, CD5 function-blocking MAb treatment enhanced the capacity of CD8 T cells to kill 4T1-mouse tumour cells in an ex vivo assay. These data support the potential of blockade of CD5 function to enhance T cell-mediated anti-tumour immunity.
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http://dx.doi.org/10.1002/eji.201948309DOI Listing
May 2020

Plk2 Regulated by miR-128 Induces Ischemia-Reperfusion Injury in Cardiac Cells.

Mol Ther Nucleic Acids 2020 Mar 30;19:458-467. Epub 2019 Nov 30.

Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Department of Surgery, Western University, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada. Electronic address:

Ischemia-reperfusion (I/R) injury occurs during cardiac surgery and is the major factor leading to heart dysfunction and heart failure. Our previous study showed that gene and microRNA expression profiles are altered in heart grafts with extended I/R injury. In this study, we, for the first time, demonstrated that I/R injury upregulates the expression of Polo-like kinase 2 (Plk2) but decreases miR-128 expression in heart cells both in vitro and in vivo. Silencing Plk2 using small interfering RNA (siRNA) protects cells from Antimycin A-induced cell apoptosis/death. Silencing Plk2 also decreases phosphorylated p65 expression but increases Angiopoietin 1 expression. In addition, Plk2 is negatively regulated by miR-128. miR-128 exerts a protective effect on cell apoptosis similar to Plk2 siRNA in response to I/R stress. Methylation inhibitor 5-azacytidine (5-AZ) increases the expression of miR-128 and subsequently reduces Plk2 expression and cell apoptosis. In conclusion, this study demonstrated that Plk2 regulated by miR-128 induces cell apoptosis/death in response to I/R stress through activation of the nuclear factor κB (NF-κB) signal pathway. miR-128 and Plk2 are new targets for preventing cardiac I/R injury or oxidative stress-mediated injury.
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http://dx.doi.org/10.1016/j.omtn.2019.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948232PMC
March 2020

Inhibition of by 420-nm Intense Pulsed Light: Activity and the Role of Nitric Oxide in Fungal Death.

Front Pharmacol 2019 3;10:1143. Epub 2019 Oct 3.

Department of Dermatology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, China.

is a common dermatophyte of the skin. The aim of this experiment was to explore the role of nitric oxide (NO) in the inhibition of growth induced by 420-nm intense pulsed light (IPL). This study found that nitric oxide synthase (NOS) and NO levels were increased, whereas asymmetric dimethylarginine (ADMA) level, keratinase activity, and fungal viability were decreased after IPL treatment compared with the control condition . Moreover, micromorphology was damaged by IPL treatment. Fungal viability was increased, and the damage to the fungal structure was reduced after pretreatment with an NOS inhibitor (L-NMMA) compared with IPL treatment alone. Compared with IPL alone, pretreatment with L-NMMA decreased NOS expression and NO level and increased keratinase activity. We found that 420-nm IPL treatment can inhibit the growth of by regulating NO .
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http://dx.doi.org/10.3389/fphar.2019.01143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785631PMC
October 2019

Supplementing preservation solution with mitochondria-targeted H S donor AP39 protects cardiac grafts from prolonged cold ischemia-reperfusion injury in heart transplantation.

Am J Transplant 2019 11 3;19(11):3139-3148. Epub 2019 Sep 3.

Department of Pathology, Western University, Ontario, Canada.

Heart transplant has been accepted as the standard treatment for end-stage heart failure. Because of its susceptibility to ischemia-reperfusion injury, the heart can be preserved for only 4 to 6 hours in cold static preservation solutions. Prolonged ischemia time is adversely associated with primary graft function and long-term survival. New strategies to preserve donor hearts are urgently needed. We demonstrate that AP39, a mitochondria-targeting hydrogen sulfide donor, significantly increases cardiomyocyte viability and reduces cell apoptosis/death after cold hypoxia/reoxygenation in vitro. It also decreases gene expression of proinflammatory cytokines and preserves mitochondria function. Using an in vivo murine heart transplant model, we show that preserving donor hearts with AP39-supplemented University of Wisconsin solution (n = 7) significantly protects heart graft function, measured by quantitative ultrasound scan, against prolonged cold ischemia-reperfusion injury (24 hours at 4°C), along with reducing tissue injury and fibrosis. Our study demonstrates that supplementing preservation solution with AP39 protects cardiac grafts from prolonged ischemia, highlighting its therapeutic potential in preventing ischemia-reperfusion injury in heart transplant.
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http://dx.doi.org/10.1111/ajt.15539DOI Listing
November 2019

DMBX1 promotes tumor proliferation and regulates cell cycle progression via repressing OTX2-mediated transcription of p21 in lung adenocarcinoma cell.

Cancer Lett 2019 07 27;453:45-56. Epub 2019 Mar 27.

Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, China. Electronic address:

Lung adenocarcinoma (LUAD) was the predominant histological subtype of lung cancer, with poor prognosis. By analyzing the TCGA dataset, we found that DMBX1 (diencephalon/mesencephalon homeobox 1), a member of the bicoid sub-family of homeodomain-containing transcription factors, was overexpressed in LUAD and correlated with poorer prognosis and more advanced clinicopathological features of LUAD patients. Silencing of DMBX1 inhibited proliferation of LUAD and induced G1/S cell cycle arrest, whereas ectopic expression of DMBX1 enhanced tumor growth of LUAD and promoted G1/S cell cycle exit. Furtherly we found that the function of DMBX1 was dependent on p21 (CDKN1A), a key regulator of G1/S cell cycle progression. Co-IP assay revealed that DMBX1 directly bound to another homeobox transcription factor, OTX2. ChIP and luciferase reporter assay confirmed that OTX2 directly interacted with the promoter region of p21 to enhance its transcription, and DMBX1 repressed OTX2-mediated transcription of p21. Our study reveals that DMBX1 plays an oncogenic role in LUAD by repressing OTX2-mediated transcription of p21 and the results may provide new therapeutic targets for LUAD patients.
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http://dx.doi.org/10.1016/j.canlet.2019.03.045DOI Listing
July 2019

A clinical, biologic and mechanistic analysis of the role of ZNF692 in cervical cancer.

Gynecol Oncol 2019 02 19;152(2):396-407. Epub 2018 Nov 19.

Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, the Affiliated Cancer Hospital of Nanjing Medical University, China; Jiangsu Key Laboratory of Molecular and Translational Cancer Research, China. Electronic address:

Objective: Cervical cancer (CC) is the most common malignancy in women. The zinc finger protein 692 (ZNF692) has been identified as a transcription factor and its aberrant expression participates in tumorigenesis of various cancers. However, its biological function and molecular mechanisms in cervical cancer remain unclear.

Methods: Microarrays were analysed by immunohistochemistry (IHC) to investigate the expression of ZNF692 in cervical cancer and its relationship with clinicopathologic characteristics. siRNAs and expression plasmids were used to reveal the biological function of ZNF692 in CC and subcutaneous xenograft model to examine the role of ZNF692 in vivo. Chromatin Immunoprecipitation and luciferase reporter assay were performed to ascertain whether ZNF692 binds to the promoter region of p27.

Results: By analyzing The Cancer Genome Atlas (TCGA) dataset, we confirmed ZNF692 as a potential oncogene in CC. ZNF692 expression was up-regulated in CC tissues compared with that in adjacent normal tissues, and its overexpression was correlated with poor clinicopathologic characteristics. Moreover, ZNF692 promoted the proliferation, migration and invasion of CC cells both in vitro and in vivo. Regarding molecular mechanisms, up-regulation of ZNF692 was found to enhance the G1/S transition via regulating the p27/P-CDK2 signal pathway in CC cells.

Conclusion: ZNF692 promotes CC cells proliferation and invasion through suppressing p27 transcription by directly binding its promoter region, which suggests that ZNF692 may serve as an underlying therapeutic target and prognostic marker in CC.
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http://dx.doi.org/10.1016/j.ygyno.2018.11.022DOI Listing
February 2019

GDF15 Regulates Malat-1 Circular RNA and Inactivates NFκB Signaling Leading to Immune Tolerogenic DCs for Preventing Alloimmune Rejection in Heart Transplantation.

Front Immunol 2018 30;9:2407. Epub 2018 Oct 30.

Departments of Cardiovascular Surgery, Jilin University, Changchun, China.

Recombinant human growth differentiation factor 15 (rhGDF15) affects dendritic cell (DC) maturation. However, whether GDF15 is expressed in DCs and its roles and signaling in DCs remain largely unknown. It is unclear whether GDF15-DCs can induce immune tolerance in heart transplantation (HT). This study aims to understand the impact of endogenous GDF15 on DC's development, function, underlying molecular mechanism including circular RNA (circRNA). This study will also explore GDF15-DC-mediated immune modulation in HT. Bone marrow (BM) derived DCs were cultured and treated to up- or down regulate GDF15 expression. Phenotype and function of DCs were detected. Expression of genes and circRNAs was determined by qRT-PCR. The signaling pathways activated by GDF15 were examined. The impact of GDF15 treated DCs on preventing allograft immune rejection was assessed in a MHC full mismatch mouse HT model. Our results showed that GDF15 was expressed in DCs. Knockout of GDF15 promoted DC maturation, enhanced immune responsive functions, up-regulated malat-1 circular RNA (circ_Malat 1), and activated the nuclear factor kappa B (NFκB) pathway. Overexpression of GDF15 in DCs increased immunosuppressive/inhibitory molecules, enhanced DCs to induce T cell exhaustion, and promoted Treg generation through IDO signaling. GDF15 utilized transforming growth factor (TGF) β receptors I and II, not GFAL. Administration of GDF15 treated DCs prevented allograft rejection and induced immune tolerance in transplantation. In conclusion, GDF15 induces tolerogenic DCs (Tol-DCs) through inhibition of circ_Malat-1 and the NFκB signaling pathway and up-regulation of IDO. GDF15-DCs can prevent alloimmune rejection in HT.
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http://dx.doi.org/10.3389/fimmu.2018.02407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218625PMC
October 2019

Circular RNA in cardiovascular disease.

J Cell Physiol 2019 05 20;234(5):5588-5600. Epub 2018 Oct 20.

Department of Pathology, Western University, Ontario, Canada.

Circular RNA (circRNA) are endogenous transcripts that display differential expression across species, developmental stages, and pathologies. Their lack of free ends confers increased stability when compared with linear transcripts, making them ideal candidates for future diagnostic biomarkers and therapeutic interventions. Increasing evidence has implicated circRNA in the pathogenesis of multiple cardiovascular diseases. In this paper, we summarize current understanding of circRNA biogenesis, properties, expression profiles, detection methods, functions, and their implication in cardiac pathologies including/ischemia reperfusion injury, myocardial infarction, cardiac senescence, cardiac fibrosis, cardiomyopathy, cardiac hypertrophy and heart failure, atherosclerosis, coronary artery disease, and aneurysm.
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http://dx.doi.org/10.1002/jcp.27384DOI Listing
May 2019

SNAP23 suppresses cervical cancer progression via modulating the cell cycle.

Gene 2018 Oct 23;673:217-224. Epub 2018 Jun 23.

Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, PR China; Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, PR China.

Objective: Cervical cancer (CC) is one of the most common gynecologic tumors in women worldwide, with poor prognosis and low survival rate. In this study, we identified SNAP23 as a potential tumor suppressor gene in CC.

Methods: The expression of SNAP23 in tissues and cell lines were measured by qRT-PCR, western blot and IHC. Knockdown of SNAP23 by siRNA and ectopic expression of SNAP23 by overexpression plasmid were performed to observe the biological function of SNAP23 in CC. Xenograft nude mice models were established to measure its function in vivo.

Results: SNAP23 was downregulated in CC tissues and had a negative correlation with advanced clinical characteristics. Ectopic expression of SNAP23 suppressed malignant phonotype of CC while knockdown of SNAP23 promoted the progression of CC in vitro. The flow cytometry analysis revealed that SNAP23 exerted its tumor suppressor activity via inducing G2/M cell cycle arrest. Moreover, xenograft tumor models showed that SNAP23 suppresses tumor growth in vivo.

Conclusions: Our results revealed that SNAP23 suppressed progression of CC and induced cell cycle G2/M arrest via upregulating p21 and downregulating CyclinB1.
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http://dx.doi.org/10.1016/j.gene.2018.06.028DOI Listing
October 2018

Determining the optimal parameters of 420-nm intense pulsed light on Trichophyton rubrum growth in vitro.

Lasers Med Sci 2018 Nov 23;33(8):1667-1671. Epub 2018 Apr 23.

Department of Dermatology, Shunde Hospital, Southern Medical University, Foshan, 528300, China.

The effect of and the optimal parameters for intense pulsed light (IPL) with a 420-nm filter on an isolate of the fungus Trichophyton rubrum (T. rubrum) were examined in vitro. Colonies of T. rubrum were irradiated by using 420-nm IPL with various pulse numbers and energies. Colony areas were photographed and compared with those of untreated colonies to assess growth inhibition. Statistically significant inhibition of T. rubrum growth was detected in colonies treated with 12 pulses of greater than or equal to 12 J/cm. The optimal parameters of 420-nm IPL were 12 pulses of 12 J/cm. However, more in vitro and in vivo studies are necessary to investigate and explore this mechanism to determine whether IPL would have a potential use in the treatment of fungal infections of the skin.
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http://dx.doi.org/10.1007/s10103-018-2512-yDOI Listing
November 2018

Salvianolic Acids for Injection (SAFI) promotes functional recovery and neurogenesis via sonic hedgehog pathway after stroke in mice.

Neurochem Int 2017 Nov 5;110:38-48. Epub 2017 Sep 5.

Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China.

There is a pressing need of developing approaches for delayed post-stroke therapy for patients who fail to receive thrombolysis within the narrow time window. Neuroprotection of Salvianolic Acids for Injection (SAFI) for cerebral ischemia-reperfusion injury in acute phase has been well documented. The current study was to determine the influence of SAFI at the subacute phase after stroke in mice, and to elucidate the underlying mechanisms. Adult male C57BL/6 mice were subjected to permanent occlusion of the distal middle cerebral artery (dMCAO), followed by daily intraperitoneal injection of SAFI 24 h after stroke for 14 days. Motor behavior was measured by neurological function evaluations weekly, and proliferation, migration, survival and differentiation of neural progenitor cells (NPCs) were examined with immunohistochemistry. Sonic hedgehog (Shh) inhibitor cyclopamine (CYC) was injected to determine the involvement of Shh pathway in the therapeutic effects of SAFI. The results showed that SAFI led to dramatic brain functional improvement, elevated NPCs proliferation, and prompted long-term survival of newborn neurons in the subventricular zone (SVZ). Up-regulation of Shh, Ptch and nuclear translocation of Gli1 were observed in the peri-infarct region, accompanied with robust production of Brain derived neurotrophic factor (BDNF) and Nerve growth factor (NGF). Simultaneous administration with CYC strikingly attenuated the beneficial outcomes of SAFI as well as abolished SAFI induced BDNF and NGF production. Collectively, our study demonstrated SAFI significantly promoted long-term functional recovery and neurogenesis, which might be dependent on Shh signaling mediated BDNF and NGF production. Therefore, SAFI might serve as a potential clinically translatable therapy during recovery stage after stroke.
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http://dx.doi.org/10.1016/j.neuint.2017.09.001DOI Listing
November 2017

Salvianolic acids enhance cerebral angiogenesis and neurological recovery by activating JAK2/STAT3 signaling pathway after ischemic stroke in mice.

J Neurochem 2017 10 14;143(1):87-99. Epub 2017 Sep 14.

Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.

Post-stroke angiogenesis facilitates neurovascular remodeling process and promotes neurological recovery. Proangiogenic effects of Salvianolic acids (Sals) have been reported in various ischemic disorders. However, the underlying mechanisms are still poorly understood. Previous studies of our laboratory have demonstrated that activating Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway is involved in the protection against cerebral ischemia/reperfusion injury. In this study, we investigated the impacts of Sals on angiogenesis and long-term neurological recovery after ischemic stroke as well as the potential mechanisms. Male mice subjected to permanent distal middle cerebral artery occlusion were administrated with Sals, 5-bromo-2'-deoxyuridine, and JAK2 inhibitor AG490 once daily from day 1 to day 14 after distal middle cerebral artery occlusion. Compared with the control group, Sals treatment significantly improved neurological recovery at day 14 and 28 after ischemic stroke. Sals enhanced post-stroke angiogenesis, pericytes and astrocytic endfeet covered ratio in the peri-infarct area. The JAK2/STAT3 signaling pathway was activated by Sals in the angiogenesis process, and inhibition of JAK2/STAT3 signaling blocked the effects of Sals on post-stroke angiogenesis and neurological recovery as well as abolished the mediation of proangiogenic factors. In summary, these data suggest that Sals administration enhances cerebral angiogenesis and promotes neurological recovery after ischemic stroke, mediated by the activation of JAK2/STAT3 signaling pathway.
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http://dx.doi.org/10.1111/jnc.14140DOI Listing
October 2017

ZNF692 promotes proliferation and cell mobility in lung adenocarcinoma.

Biochem Biophys Res Commun 2017 09 29;490(4):1189-1196. Epub 2017 Jun 29.

Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, 210009, PR China; Department of Thoracic Surgery, Jiangsu Cancer Hospital, Institute Affiliated to Nanjing Medical University, Cancer Institute of Jiangsu Province, Baiziting 42, Xuanwu District, Nanjing, 210009, PR China. Electronic address:

By analyzing The Cancer Genome Atlas (TCGA) datasets, we discovered that the zinc finger protein 692 (ZNF692) were over-expressed in Lung adenocarcinoma (LUAD) tissues compared to adjacent non-tumor tissues (P < 0.0001). In this study, we investigated the function of ZNF692 in the progression of LUAD. We found that ZNF692 knockdown inhibited LUAD cells proliferation, migration, and invasion both in vitro and in vivo. And LUAD cell apoptosis was induced following the down-regulation of ZNF692. Our results show that ZNF692 is over-expressed in LUAD tissues compared to adjacent normal tissues, and hyper-expression of ZNF692 in LUAD is an independent risk factor for worse overall survival in LUAD patients (HR: 8.800, 95%CI: 1.082-71.560, P = 0.042) by Tissue Microarray stain assay (TMA). GO analysis indicated that most genes were enriched in metabolic process which were associated highly with ZNF692 levels. Collectively, our results suggested that ZNF692 may serve as a potential oncogene and biomarker in LUAD by influencing cell metabolism.
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http://dx.doi.org/10.1016/j.bbrc.2017.06.180DOI Listing
September 2017

Growth Differentiation Factor-15 Deficiency Augments Inflammatory Response and Exacerbates Septic Heart and Renal Injury Induced by Lipopolysaccharide.

Sci Rep 2017 04 21;7(1):1037. Epub 2017 Apr 21.

Department of Pathology, Western University, London, ON, Canada.

Septic acute kidney injury (AKI) and myocardial dysfunction are leading causes of mortality with no accepted method of therapy. In this study we demonstrate the role of growth differentiating factor 15 (GDF15) in septic AKI and myocardial dysfunction using a murine lipopolysaccharide (LPS)-induced sepsis model and an in vitro cell culture system. Data show that GDF15 deficiency augments inflammatory response and exacerbates renal and cardiac injury induced by LPS, while over-expression of GDF15 protects the kidney and heart from LPS-induced organ dysfunction. Therefore, this study highlights the therapeutic potential of GDF15 in the treatment of endotoxin-induced sepsis.
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http://dx.doi.org/10.1038/s41598-017-00902-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430818PMC
April 2017

Over-expression of growth differentiation factor 15 (GDF15) preventing cold ischemia reperfusion (I/R) injury in heart transplantation through Foxo3a signaling.

Oncotarget 2017 May;8(22):36531-36544

Department of Pathology, Western University, Ontario, Canada.

Ischemia reperfusion (I/R) injury which inevitably occurs during heart transplantation is the major factor leading to organ failure and graft rejection. In order to develop new therapies to prevent I/R injury, we used both a murine heart transplantation model with 24 hour cold I/R and an in vitro cell culture system to determine whether growth differentiation factor 15 (GDF15) is a protective factor in preventing I/R injury in heart transplantation and to further investigate underlying mechanisms of I/R injury. We found that cold I/R caused severe damage to the endocardium, epicardium and myocardium of heart grafts from wild type C57BL/6 mice, whereas grafts from GDF15 transgenic (TG) mice showed less damage as demonstrated by decreased cell apoptosis/death, decreased neutrophils infiltration and the preservation of the normal structure of the heart. Over-expression of GDF15 reduced expression of phosphorylated RelA p65, pre-inflammatory and pro-apoptotic genes while it enhanced Foxo3a phosphorylation in vitro and in vivo. Over-expression of GDF15 inhibited cell apoptosis/death and reduced neutrophil infiltration. In conclusion, this study, for the first time, demonstrates that GDF15 is a promising target for preventing cold I/R injury in heart transplantation. This study also shows that the resultant protective effects are mediated by the Foxo3 and NFκB signaling pathways.
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http://dx.doi.org/10.18632/oncotarget.16607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482674PMC
May 2017

The effect of fenofibric acid on the pharmacokinetics and pharmacodynamics of warfarin in rats.

Xenobiotica 2018 Apr 31;48(4):400-406. Epub 2017 Mar 31.

a Clinical Pharmacokinetics Research Laboratory, China Pharmaceutical University , Nanjing , China and.

1. Case reports have shown that coadministration of fenofibric acid (FA) could increase bleeding risks of warfarin, but the mechanisms remained unknown. We therefore investigated the pharmacokinetic and pharmacodynamic interaction between warfarin and FA in rats. 2. Rats received warfarin alone (2 mg/kg) or coadministered with FA (100 mg/kg). FA significantly increased the exposure to warfarin, and decreased that to 7-hydroxywarfarin in rats nearly by two-fold, meanwhile increased C and prolonged t of warfarin. Anticoagulant activity significantly increased, with prothrombin time (PT) up to 199 ± 33 s in coadministered group (approximately ten-fold compared with rats received warfarin alone). Incubation experiments illustrated FA inhibited CYP2C6 and CYP3A1/2 with the IC50 values of 6.98 and 16.14 μM, and inhibited the metabolism of warfarin (K value of 2.21 μM). Meanwhile, FA decreased the plasma protein binding of warfarin in vitro. 3. Our data suggested that the altered pharmacokinetics and pharmacodynamics of warfarin in rats was primarily attributed to the inhibition of metabolism. Anticoagulant activity monitoring or warfarin dose lowering needs to be considered when patients are coadministered with FA.
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http://dx.doi.org/10.1080/00498254.2017.1306760DOI Listing
April 2018

Synergistic suppression of autoimmune arthritis through concurrent treatment with tolerogenic DC and MSC.

Sci Rep 2017 02 23;7:43188. Epub 2017 Feb 23.

College of Basic Medical Sciences and Institute of Immunotherapy of Nanchang University, and Jiangxi Academy of Medical Sciences, Nanchang, China.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive immune-mediated joint deterioration. Current treatments are not antigen specific and are associated with various adverse. We have previously demonstrated that tolerogenic dendritic cells (Tol-DC) are potent antigen-specific immune regulators, which hold great promise in immunotherapy of autoimmune diseases. In this study, we aimed to develop new immunotherapy by combining Tol-DC and mesenchymal stem cells (MSC). We demonstrated that RelB gene silencing resulted in generation of Tol-DC that suppressed T cell responses and selectively promoted Treg generation. The combination of MSC synergized the tolerogenic capacity of Tol-DC in inhibition of T cell responses. In murine collagen-induced arthritis (CIA) model, we demonstrated that progression of arthritis was inhibited with administration of RelB gene-silenced Tol-DC or MSC. This therapeutic effect was remarkably enhanced with concurrent treatment of combination Tol-DC and MSC as demonstrated by improved clinical symptoms, decreased clinical scores and attenuated joint damage. These therapeutic effects were associated with suppression of CII-specific T cell responses, polarization of Th and inhibition of proinflammatory cytokines, and reduced cartilage degeneration. This study for the first time demonstrates a new approach to treat autoimmune inflammatory joint disease with concurrent treatment of RelB gene-silenced Tol-DC and MSC.
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http://dx.doi.org/10.1038/srep43188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322386PMC
February 2017

Revisiting the male genetic landscape of China: a multi-center study of almost 38,000 Y-STR haplotypes.

Hum Genet 2017 05 30;136(5):485-497. Epub 2017 Jan 30.

School of Forensic Medicine, China Medical University, Shenyang, People's Republic of China.

China has repeatedly been the subject of genetic studies to elucidate its prehistoric and historic demography. While some studies reported a genetic distinction between Northern and Southern Han Chinese, others showed a more clinal picture of small differences within China. Here, we investigated the distribution of Y chromosome variation along administrative as well as ethnic divisions in the mainland territory of the People's Republic of China, including 28 administrative regions and 19 recognized Chinese nationalities, to assess the impact of recent demographic processes. To this end, we analyzed 37,994 Y chromosomal 17-marker haplotype profiles from the YHRD database with respect to forensic diversity measures and genetic distance between groups defined by administrative boundaries and ethnic origin. We observed high diversity throughout all Chinese provinces and ethnicities. Some ethnicities, including most prominently Kazakhs and Tibetans, showed significant genetic differentiation from the Han and other groups. However, differences between provinces were, except for those located on the Tibetan plateau, less pronounced. This discrepancy is explicable by the sizeable presence of Han speakers, who showed high genetic homogeneity all across China, in nearly all studied provinces. Furthermore, we observed a continuous genetic North-South gradient in the Han, confirming previous reports of a clinal distribution of Y chromosome variation and being in notable concordance with the previously observed spatial distribution of autosomal variation. Our findings shed light on the demographic changes in China accrued by a fast-growing and increasingly mobile population.
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http://dx.doi.org/10.1007/s00439-017-1759-xDOI Listing
May 2017
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