Publications by authors named "Dongbo Qiu"

8 Publications

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Human DUBs' gene expression and regulation in antiviral signaling in response to poly (I:C) treatment.

Mol Immunol 2021 01 2;129:45-52. Epub 2020 Dec 2.

Cell-gene Therapy Translational Medicine Research Center, Biotherapy center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China. Electronic address:

Type I interferons (IFNs) play a central role in host defense against viral infection. Multiple posttranslational modifications including ubiquitination and deubiquitination regulate the function of diverse molecules in type I IFN signaling. Many ubiquitin ligase enzymes, such as those of the TRAF and TRIM families, have been shown to participate in the production of type I IFNs and inflammatory cytokines. However, the function of deubiquitinating enzymes (DUBs), a protein family that counteracts the action of protein ubiquitination, on the regulation of antiviral immune responses is not well understood. In this study, we used the broad-spectrum DUB inhibitor G5 to reveal their function in antiviral signaling, and then systematically analyzed mRNA expression of the DUB genes upon poly (I:C) treatment in THP-1 cells. Based on this analysis, we cloned some DUB genes whose expression changed and determined their function in antiviral signaling. Taken together, we present a comprehensive DUB gene expression analysis in THP-1 cells, and suggest the involvement of this family of proteins in the regulation of host antiviral activities.
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http://dx.doi.org/10.1016/j.molimm.2020.11.006DOI Listing
January 2021

Targeting Nestin hepatic stellate cells ameliorates liver fibrosis by facilitating TβRI degradation.

J Hepatol 2021 May 17;74(5):1176-1187. Epub 2020 Nov 17.

Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Cell-gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address:

Background & Aims: Liver fibrosis is a wound healing response that arises from various aetiologies. The intermediate filament protein Nestin has been reported to participate in maintaining tissue homeostasis during wound healing responses. However, little is known about the role Nestin plays in liver fibrosis. This study investigated the function and precise regulatory network of Nestin during liver fibrosis.

Methods: Nestin expression was assessed via immunostaining and quantitative real-time PCR (qPCR) in fibrotic/cirrhotic samples. The induction of Nestin expression by transforming growth factor beta (TGFβ)-Smad2/3 signalling was investigated through luciferase reporter assays. The functional role of Nestin in hepatic stellate cells (HSCs) was investigated by examining the pathway activity of profibrogenic TGFβ-Smad2/3 signalling and degradation of TGFβ receptor I (TβRI) after interfering with Nestin. The in vivo effects of knocking down Nestin were examined with an adeno-associated virus vector (serotype 6, AAV6) carrying short-hairpin RNA targeting Nestin in fibrotic mouse models.

Results: Nestin was mainly expressed in activated HSCs and increased with the progression of liver fibrosis. The profibrogenic pathway TGFβ-Smad2/3 induced Nestin expression directly. Knocking down Nestin promoted caveolin 1-mediated TβRI degradation, resulting in TGFβ-Smad2/3 pathway impairment and reduced fibrosis marker expression in HSCs. In AAV6-treated murine fibrotic models, knocking down Nestin resulted in decreased levels of inflammatory infiltration, hepatocellular damage, and a reduced degree of fibrosis.

Conclusion: The expression of Nestin in HSCs was induced by TGFβ and positively correlated with the degree of liver fibrosis. Knockdown of Nestin decreased activation of the TGFβ pathway and alleviated liver fibrosis both in vitro and in vivo. Our data demonstrate a novel role of Nestin in controlling HSC activation in liver fibrosis.

Lay Summary: Liver fibrosis has various aetiologies but represents a common process in chronic liver diseases that is associated with high morbidity and mortality. Herein, we demonstrate that the intermediate filament protein Nestin plays an essential profibrogenic role in liver fibrosis by forming a positive feedback loop with the TGFβ-Smad2/3 pathway, providing a potential therapeutic target for the treatment of liver fibrosis.
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http://dx.doi.org/10.1016/j.jhep.2020.11.016DOI Listing
May 2021

Wogonin Suppresses IL-10 Production in B Cells via STAT3 and ERK Signaling Pathway.

J Immunol Res 2020 1;2020:3032425. Epub 2020 Jun 1.

The Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.

Wogonin (5,7-dihydroxy-8-methoxyflavone) is an ingredient of the extracts from Scutellaria baicalensis, which has documented a wide spectrum of anti-inflammatory and antitumor activities, including inhibiting regulatory T cells, regulating effector T cell functions, and mediating macrophage immunity. However, the potential effect of Wogonin on B cells has not been fully understood. Here, our results showed that Wogonin inhibited IL-10 secretion in B cells. When purified B cells were activated by lipopolysaccharide (LPS) in vitro, the amount of IL-10 production in supernatant was decreased by Wogonin significantly. The protective role of B cells on dextran sulfate sodium- (DSS-) induced colitis was alleviated after exposure to Wogonin. Furthermore, administration of Wogonin on LPS-treated B cells suppressed phosphorylation of STAT3 and ERK, but not AKT. Interestingly, among those IL-10 signaling-associated transcription factors, mRNA and protein levels of Hif-1 were specifically decreased by Wogonin. Overall, our study indicates that Wogonin suppresses potentially IL-10 production in B cells via inhibition of the STAT3 and ERK signaling pathway as well as inhibition of mRNA and protein levels of the transcription factor Hif-1. These results provide novel and potential molecular targets of Wogonin in B cells and help us further understand its mechanism of action, which could potentially improve its clinical application in the future.
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http://dx.doi.org/10.1155/2020/3032425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285295PMC
June 2020

Generation of hepatocyte-like cells from human urinary epithelial cells and the role of autophagy during direct reprogramming.

Biochem Biophys Res Commun 2020 06 18;527(3):723-729. Epub 2020 May 18.

Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address:

Somatic cells can be directly reprogrammed into other cell lineages, which holds great promise for regenerative medicine. However, low efficiency and obscure mechanism hinder the application of direct reprogramming. Here, we show that overexpressing the hepatic-specific transcription factors (TFs) HNF1α, FOXA3, and GATA4 was sufficient to convert human urinary epithelial cells (hUCs) into induced hepatocyte-like cells (iHeps). The obtained iHeps were confirmed to express various hepatocyte-specific genes with multiple mature hepatocyte functions. Moreover, autophagy-related genes P62, ULK1, BECN1, VPS34, and LC3B were upregulated in the early stage of reprogramming and knockout of P62 and BECN1 in hUCs with CRISPR/Cas9 technology increased the efficiency of direct reprogramming. Collectively, we established a non-invasive approach to convert hUCs into iHeps and provided a glimpse into the role of autophagy in this process.
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http://dx.doi.org/10.1016/j.bbrc.2020.03.119DOI Listing
June 2020

mRNA modification orchestrates cancer stem cell fate decisions.

Mol Cancer 2020 02 26;19(1):38. Epub 2020 Feb 26.

Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China.

Despite their small numbers, cancer stem cells play a central role in driving cancer cell growth, chemotherapeutic resistance, and distal metastasis. Previous studies mainly focused on how DNA or histone modification determines cell fate in cancer. However, it is still largely unknown how RNA modifications orchestrate cancer cell fate decisions. More than 170 distinct RNA modifications have been identified in the RNA world, while only a few RNA base modifications have been found in mRNA. Growing evidence indicates that three mRNA modifications, inosine, 5-methylcytosine, and N-methyladenosine, are essential for the regulation of spatiotemporal gene expression during cancer stem cell fate transition. Furthermore, transcriptome-wide mapping has found that the aberrant deposition of mRNA modification, which can disrupt the gene regulatory network and lead to uncontrollable cancer cell growth, is widespread across different cancers. In this review, we try to summarize the recent advances of these three mRNA modifications in maintaining the stemness of cancer stem cells and discuss the underlying molecular mechanisms, which will shed light on the development of novel therapeutic approaches for eradicating cancer stem cells.
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http://dx.doi.org/10.1186/s12943-020-01166-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043046PMC
February 2020

Mesenchymal stromal cells-derived matrix Gla protein contribute to the alleviation of experimental colitis.

Cell Death Dis 2018 06 7;9(6):691. Epub 2018 Jun 7.

Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Crohn's disease (CD) is a chronic inflammatory bowel disease that is difficult to treat. However, previous preclinical and clinical studies have shown that mesenchymal stromal cells (MSCs) are a promising therapeutic approach, whereas the exact underlying molecular mechanisms of MSCs in treating CD remain unclear. Furthermore, the heterogeneity of MSCs, as well as the in vivo microenvironments may influence the therapeutic efficacy. In our previous study, we found that a subpopulation of mouse MSCs with a high expression of matrix Gla protein (MGP), one of the members of vitamin K-dependent protein family, possessed better immunoregulatory properties. Therefore, in this study we investigate whether the abundant MSCs-derived MGP participate in the therapeutic mechanisms for MSCs treating CD. Obvious suppression of cell proliferation and cytokine production in T cells were observed in vitro through MSCs-derived MGP. Moreover, MGP alleviated the clinical and histopathological severity of colonic inflammation in mouse experimental colitis models to a remarkable degree. Our results indicate that MGP might be a novel important mediator of MSCs-mediated immunomodulation in treating CD.
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http://dx.doi.org/10.1038/s41419-018-0734-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992143PMC
June 2018

Highly efficient and expedited hepatic differentiation from human pluripotent stem cells by pure small-molecule cocktails.

Stem Cell Res Ther 2018 03 9;9(1):58. Epub 2018 Mar 9.

Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, People's Republic of China.

Background: The advent of human-induced pluripotent stem cells holds great promise for producing ample individualized hepatocytes. Although previous efforts have succeeded in generating hepatocytes from human pluripotent stem cells in vitro by viral-based expression of transcription factors and/or addition of growth factors during the differentiation process, the safety issue of viral transduction and high cost of cytokines would hinder the downstream applications. Recently, the use of small molecules has emerged as a powerful tool to induce cell fate transition for their superior stability, safety, cell permeability, and cost-effectiveness.

Methods: In the present study, we established a novel efficient hepatocyte differentiation strategy of human pluripotent stem cells with pure small-molecule cocktails. This method induced hepatocyte differentiation in a stepwise manner, including definitive endoderm differentiation, hepatic specification, and hepatocyte maturation within only 13 days.

Results: The differentiated hepatic-like cells were morphologically similar to hepatocytes derived from growth factor-based methods and primary hepatocytes. These cells not only expressed specific hepatic markers at the transcriptional and protein levels, but also possessed main liver functions such as albumin production, glycogen storage, cytochrome P450 activity, and indocyanine green uptake and release.

Conclusions: Highly efficient and expedited hepatic differentiation from human pluripotent stem cells could be achieved by our present novel, pure, small-molecule cocktails strategy, which provides a cost-effective platform for in vitro studies of the molecular mechanisms of human liver development and holds significant potential for future clinical applications.
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http://dx.doi.org/10.1186/s13287-018-0794-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845228PMC
March 2018

Klf2 and Tfcp2l1, Two Wnt/β-Catenin Targets, Act Synergistically to Induce and Maintain Naive Pluripotency.

Stem Cell Reports 2015 Sep 28;5(3):314-22. Epub 2015 Aug 28.

Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, University of Southern California, Los Angeles, CA 90033, USA. Electronic address:

Activation of Wnt/β-catenin signaling can induce both self-renewal and differentiation in naive pluripotent embryonic stem cells (ESCs). To gain insights into the mechanism by which Wnt/β-catenin regulates ESC fate, we screened and characterized its downstream targets. Here, we show that the self-renewal-promoting effect of Wnt/β-catenin signaling is mainly mediated by two of its downstream targets, Klf2 and Tfcp2l1. Forced expression of Klf2 and Tfcp2l1 can not only induce reprogramming of primed state pluripotency into naive state ESCs, but also is sufficient to maintain the naive pluripotent state of ESCs. Conversely, downregulation of Klf2 and Tfcp2l1 impairs ESC self-renewal mediated by Wnt/β-catenin signaling. Our study therefore establishes the pivotal role of Klf2 and Tfcp2l1 in mediating ESC self-renewal promoted by Wnt/β-catenin signaling.
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http://dx.doi.org/10.1016/j.stemcr.2015.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618593PMC
September 2015