Publications by authors named "Qiuju Han"

60 Publications

miR-590-5p affects chondrocyte proliferation, apoptosis, and inflammation by targeting FGF18 in osteoarthritis.

Am J Transl Res 2021 15;13(8):8728-8741. Epub 2021 Aug 15.

Department of Orthopaedics, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University Jinan, Shandong Province, China.

Objective: To investigate the potential miRNA targeting FGF18, and its role in regulating the proliferation, apoptosis and inflammation in human primary chondrocytes.

Methods: The normal human chondrocytes were induced by IL-1β to mimic OA . qPCR and Western blotting were performed to evaluate the expression of FGF18. Target Scan analysis was performed to predict the miRNA targeting FGF18. Then, the expression of miR-590-5p was quantified by qPCR in IL-1β-induced chondrocytes. After transfection of miR-590-5p mimics or inhibitors, CCK-8 assay was conducted to determine the cell viability and apoptosis-related proteins, and cartilage degeneration related biomarkers were assayed by qPCR and Western blotting. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 were determined by ELISA. The targeting relationship between miR-590-5p and FGF18 was assayed by luciferase reporter assay in IL-1β-induced chondrocytes.

Results: Target Scan analysis predicted that FGF18 is directly targeted by miR-590-5p. miR-590-5p was up-regulated, whereas FGF18 expression was inhibited in IL-1β-induced chondrocytes. miR-590-5p mimics reduced the expression of FGF18 protein, inhibited the cell viability of chondrocytes, and promoted secretion of inflammatory factors in chondrocytes, while miR-590-5p inhibitors increased FGF18 levels in IL-1β-treated chondrocytes. Furthermore, expression of inflammatory factors in chondrocytes was reduced by miR-590-5p inhibitors. The luciferase reporter assay showed that miR-590-5p could target FGF18.

Conclusions: miR-590-5p promotes OA progression by targeting FGF18, which serves as a potential therapeutic target for OA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430182PMC
August 2021

Chitosan Nanovaccines as Efficient Carrier Adjuvant System for IL-12 with Enhanced Protection Against HBV.

Int J Nanomedicine 2021 21;16:4913-4928. Epub 2021 Jul 21.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China.

Purpose: Alum adjuvant in HBV prophylactic vaccines is poor in inducing cellular immunity with the inhibition of IL-12 secretion, and approximately 5-10% of immunised individuals fail to clear HBV upon infection. IL-12 plasmids (pIL-12) as adjuvants enhance significant humoral and cellular immune response in vaccines. However, finding a novel delivery system to protect pIL-12 from enzymatic degradation and achieve efficient delivery remains a major challenge.

Methods: We prepared the chitosan nanovaccine-loaded IL-12 expression plasmid (termed as "Ng(-)pIL-12") and analysed the physicochemical properties, encapsulation efficiency and safety. Then, we evaluated the efficiency of Ng(-)pIL-12 for prophylactic HBV vaccine. Serum samples were collected and analysed for IL-12, HBsAg, anti-HBs IgG, IgG1 and IgG2b. Liver tissues were collected and analysed for HBV DNA and RNA. BMDCs and lymphocytes were collected and analysed for HBV-specific immune responses. To further confirm the long-term protective immune response against HBV, these immunised mice were challenged with hydrodynamic injection of pAAV/HBV 1.2 plasmid on day 56 after the initiation of immunisation.

Results: Chitosan nanovaccine prepared with CS and γ-PGA could load pIL-12 effectively and safely, and IL-12 was efficiently produced in vivo. Interestingly, Ng(-)pIL-12 adjuvant combined with HBsAg induced higher levels of anti-HBs IgG, IgG1 and IgG2b, promoted maturation and presentation capacity of DCs, especially CD8α/CD103 DCs. Meanwhile, Ng(-)pIL-12 adjuvant generated robust HBV-specific CD8 T and CD4 T cell responses. More importantly, Ng(-)pIL-12 adjuvant triggered terminally differentiated effector memory responses with strong anti-HBV effects.

Conclusion: Chitosan nanovaccines as an efficient carrier adjuvant system for pIL-12 combined with HBsAg induced protective anti-HBs IgG and enhanced HBV-specific CD8 T and CD4 T cell responses, and achieved long-term memory response against HBV, making it a promising candidate for prophylactic HBV vaccines.
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http://dx.doi.org/10.2147/IJN.S317113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312321PMC
July 2021

HBsAg Dampened STING Associated Activation of NK Cells in HBeAg-Negative CHB Patients.

Int J Mol Sci 2021 Jul 16;22(14). Epub 2021 Jul 16.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.

NK cells play crucial roles in defending against persistent HBV. However, NK cells present dysfunction in chronic hepatitis B virus (CHB) infection, and the associated mechanism is still not fully understood. Except for the regulatory receptors, NK cells could also be regulated by the surface and intracellular pattern recognition receptors (PRRs). In the present study, we found that the level of the adaptor of DNA sensor STING in NK cells was significantly decreased in HBeAg-negative CHB patients, and it was positively associated with the degranulation ability of NK cells. Compared to NK cells from healthy donors, NK cells from HBeAg-negative CHB patients displayed a lower responsiveness to cGAMP stimulation. Further investigation showed that HBsAg could inhibit the STING expression in NK cells and suppress the response of NK cells to cGAMP. Significantly, STAT3 was identified to be a transcription factor that directly regulated STING transcription by binding to the promoter. In addition, STAT3 positively regulated the STING associated IFN-α response of NK cells. These findings suggested that STING is an important adaptor in NK cell recognition and activation, while HBsAg disturbs NK cell function by the STAT3-STING axis, providing a new mechanism of NK disability in HBeAg-negative CHB infection.
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http://dx.doi.org/10.3390/ijms22147643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304816PMC
July 2021

The Mechanisms of HBV-Induced Hepatocellular Carcinoma.

J Hepatocell Carcinoma 2021 20;8:435-450. Epub 2021 May 20.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China.

Hepatocellular carcinoma (HCC) is a common malignancy, and the hepatitis B virus (HBV) is its major pathogenic factor. Over the past decades, it has been confirmed that HBV infection could promote disease progression through a variety of mechanisms, ultimately leading to the malignant transformation of liver cells. Many factors have been identified in the pathogenesis of HBV-associated HCC (HBV-HCC), including HBV gene integration, genomic instability caused by mutation, and activation of cancer-promoting signaling pathways. As research in the progression of HBV-HCC progresses, the role of many new mechanisms, such as epigenetics, exosomes, autophagy, metabolic regulation, and immune suppression, is also being continuously explored. The occurrence of HBV-HCC is a complex process caused by interactions across multiple genes and multiple steps, where the synergistic effects of various cancer-promoting mechanisms accelerate the process of disease evolution from inflammation to tumorigenesis. In this review, we aim to provide a brief overview of the mechanisms involved in the occurrence and development of HBV-HCC, which may contribute to a better understanding of the role of HBV in the occurrence and development of HCC.
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http://dx.doi.org/10.2147/JHC.S307962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147889PMC
May 2021

A Supramolecular Strategy to Engineering a Non-photobleaching and Near-Infrared Absorbing Nano-J-Aggregate for Efficient Photothermal Therapy.

ACS Nano 2021 03 26;15(3):5032-5042. Epub 2021 Feb 26.

State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China.

The design of organic photothermal agents (PTAs) for applications face a demanding set of performance requirements, especially intense NIR-absorptivity and sufficient photobleaching resistance. J-aggregation offers a facile way to tune the optical properties of dyes, thus providing a general design platform for organic PTAs with the desired performance. Herein, we present a supramolecular strategy to build a water-stable, nonphotobleaching, and NIR-absorbing nano-PTA (J-NP) from J-aggregation of halogenated BODIPY dyes (BDP) for efficient photothermal therapy. Multiple intermolecular halogen-bonding and π-π stacking interactions triggered the formation of BDP J-aggregate, which adsorbed amphiphilic polymer chains on the surface to provide PEGylated sheetlike nano-J-aggregate (J-NS). We serendipitously discovered that the architecture of J-NS was remodeled during a long-time ultrafiltration process, generating a discrete spherical nano-J-aggregate (J-NP) with controlled size. Compared with J-NS, the remodeled J-NP significantly improved cellular uptake efficiency. J-aggregation brought J-NP striking photothermal performance, such as strong NIR-absorptivity, high photothermal conversion efficiency up to 72.0%, and favorable nonphotobleaching ability. PEGylation and shape-remodeling imparted by the polymer coating enabled J-NP to hold biocompatibility and stability , thereby exhibiting efficient antitumor photothermal activities. This work not only presents a facile J-aggregation strategy for preparing PTAs with high photothermal performance but also establishes a supramolecular platform that enables the appealing optical functions derived from J-aggregation to be applied .
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http://dx.doi.org/10.1021/acsnano.0c09993DOI Listing
March 2021

Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/β-catenin/c-Myc signaling and reprogramming glycolysis.

J Exp Clin Cancer Res 2021 Jan 6;40(1):13. Epub 2021 Jan 6.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, Shandong Province, China.

Background: Tumour-associated macrophages (TAMs) in the tumour microenvironment (TME) can promote the progression of hepatocellular carcinoma (HCC). Some tumours can be suppressed by targeting Wnt2b in tumour cells. However, the role of Wnt2b in HCC is still unknown. In particular, the role of Wnt2b-mediated signal activation in macrophage polarization in the HCC microenvironment, and the regulatory effect between Wnt and glycolysis in TAMs has not been described.

Methods: The expression of Wnt2b in TAMs was detected by qPCR and immunofluorescence. Wnt2b/β-catenin interference in HCC-TAMs was performed by lentivirus carrying targeted shRNA or TLR9 agonist. Markers related to macrophage polarization and the changes of key glycolytic enzymes expression were detected by flow cytometry and qPCR. ECAR was analysed by Seahorse analyser. MTT assay, wound healing assay, western blotting were used to evaluate the promoting effect of different HCC-TAMs on the proliferation, migration and EMT of HCC in vitro. Tumour cells and different HCC-TAMs were injected via subcutaneously into immunodeficient mice to assess the effects of CpG ODN, Wnt2b, or β-catenin on HCC-TAMs in tumour growth in vivo.

Results: Polarization-promoting factors derived from HCC cells upregulated the expression of Wnt2b in macrophages, which promoted the polarization of TAMs to M2-like macrophages by activating Wnt2b/β-catenin/c-Myc signalling. Furthermore, this process was associated with the activation of glycolysis in HCC-TAMs. These HCC-TAMs could promote the development of EMT, proliferation, and migration of HCC. In addition to silencing Wnt2b or β-catenin expression, TLR9 agonist CpG ODN downregulated the level of glycolysis and inhibited the M2 polarization of HCC-TAMs, reversing the tumour-promoting effects of TAMs in vitro and vivo.

Conclusions: As a potential target for HCC therapy, Wnt2b may play an important regulatory role for the functions of TAMs in the TME. Moreover, the TLR9 agonist CpG ODN might act as a Wnt2b signal inhibitor and can potentially be employed for HCC therapy by disturbing Wnt2b/β-catenin/c-Myc and inhibiting glycolysis in HCC-TAMs.
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http://dx.doi.org/10.1186/s13046-020-01808-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788901PMC
January 2021

Napabucasin Reduces Cancer Stem Cell Characteristics in Hepatocellular Carcinoma.

Front Pharmacol 2020 3;11:597520. Epub 2020 Dec 3.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. stem cells (CSCs) are a rare population with self-renewal and multipotent differentiation capacity, and reside among the more differentiated cancer cells. CSCs are associated with tumor recurrence, drug resistance and poor prognosis. The aim of this study was to determine the efficacy of napabucasin against HCC and elucidate the underlying molecular mechanisms. Napabucasin significantly decreased the viability of HCC cells by inducing apoptosis and cell cycle arrest. In addition, it suppressed CSC-related gene expression and spheroid formation , indicating depletion of CSCs. The anti-neoplastic effects of napabucasin was also evident in homograft tumor-bearing mouse models. Our findings provide the scientific basis of conducting clinical trials on napabucasin as a new therapeutic agent against HCC.
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http://dx.doi.org/10.3389/fphar.2020.597520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744694PMC
December 2020

STAT3: A key signaling molecule for converting cold to hot tumors.

Cancer Lett 2020 10 6;489:29-40. Epub 2020 Jun 6.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, 250012, China. Electronic address:

Tumors can be classified as cold or hot according to the degree of immune cell infiltration into tumor tissues; cold tumors are insensitive to either chemotherapy or immunotherapy and are associated with poor prognosis. Recent studies have shown that STAT3 signaling molecules hinder the conversion of cold to hot tumors by regulating immunosuppressive molecule secretion and immunosuppressive cell functions. This review aims to present the most recent studies on how STAT3 regulates cold tumor formation and discuss its research status in cancer therapy. We also present insight for designing new therapeutic strategies to "heat" tumors and provide a reference for tumor immunotherapy.
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http://dx.doi.org/10.1016/j.canlet.2020.05.035DOI Listing
October 2020

Synergetic Tumor Probes for Facilitating Therapeutic Delivery by Combined-Functionalized Peptide Ligands.

Anal Chem 2020 04 5;92(8):5650-5655. Epub 2020 Mar 5.

School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, P. R. China.

Both targeting and penetrating ability are the key characteristics for tissue probing and precise delivery. To construct an efficient nano probing and delivery system toward human epidermal growth factor receptor 2 (HER2) positive cancer, we established a nano liposomal system functionalized with a newly screened HER2 targeting peptide (HP2, YDLKEPEH) and the cell-penetrating peptide TAT simultaneously. Compared with the monofunctionalized liposomal probes, the dual-functional ones demonstrated a synergetic effect in cell uptake, drug delivery, and in vivo imaging. The improved efficacy of the synergetic system provides a prospective strategy for cancer diagnosis and therapy.
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http://dx.doi.org/10.1021/acs.analchem.0c00440DOI Listing
April 2020

Androgen Receptor (AR)-TLR4 Crosstalk Mediates Gender Disparities in Hepatocellular Carcinoma Incidence and Progression.

J Cancer 2020 1;11(5):1094-1103. Epub 2020 Jan 1.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.

Androgen receptor (AR) has a role in regulating malignancies and gender disparities in hepatocellular carcinoma (HCC). Recently, TLR4 activation is demonstrated to be required for HCC progression; however, whether and how TLR4 interacts with AR is largely unknown. The tumorigenesis was detected in female and male mice induced by DEN/CCL then TLR4 and AR signals were detected in liver tissues by qPCR and FACS. The proliferation, colony formation and migration of HCC cell treated with TLR4 agonist LPS, or/and androgen DHT were evaluated . Furthermore, the expression of TLR4 and AR was detected by IHC in tissue microarray of HCC, and correlation of AR and TLR4 was defined. Male mice are more susceptible to develop HCC than female mice. Meanwhile, we found baseline TLR4 levels were higher in male mice than in female mice. AR expression in male mice was increased by treatment with DEN/CCL. And, AR was constitutively expressed in human HCC cell lines. Dihydrotestosterone (DHT) stimulated TLR4 expression in both HepG2 and HepG2 2.15 cells, which could be blocked by silencing AR. On the other hand, treatment with LPS stimulated AR expression, but it was blocked by treatment with TLR4 antagonist and in cells deficient for TLR4. DHT treatment exacerbated TLR4-induced cellular proliferation, colony formation, migration, and invasion of HepG2 cells. The positive relationship between AR and TLR4 was confirmed in human HCC samples. DHT-AR-TLR4 signaling enhances the development of HCC cells and facilitates their migration and invasion, demonstrating a mechanism underlying gender disparity in HCC.
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http://dx.doi.org/10.7150/jca.30682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959060PMC
January 2020

TLR2 Promotes Monocyte/Macrophage Recruitment Into the Liver and Microabscess Formation to Limit the Spread of .

Front Immunol 2019 26;10:1388. Epub 2019 Jun 26.

School of Pharmaceutical Sciences, Institute of Immunopharmaceutical Sciences, Shandong University, Jinan, China.

TLR2 signaling plays a critical protective role against acute (Lm) infection by up-regulating inflammatory cytokines and promoting macrophage antimicrobial capabilities. However, the underlying mechanism by which TLR2 regulates hepatic macrophage-mediated anti-Lm immune responses remains poorly understood. In this study, we found that both the absolute number and proportion of monocyte/macrophage (Mo/MΦ) in the liver and spleen of mice were significantly lower compared to wild type mice. Changes in TLR2 signaling in both hepatocytes and Mo/MΦs were associated with the infiltration of Mo/MΦs in response to Lm-infection. Analyses by proteome profiler array and ELISA revealed that hepatocytes recruited Mo/MΦs via TLR2-dependent secretion of CCL2 and CXCL1, which was confirmed by receptor blocking and exogenous chemokine administration. Importantly, we found that TLR2 contributed to macrophage mobility in the liver through a TLR2/NO/F-actin pathway, facilitating the formation of macrophage-associated hepatic microabscesses. Moreover, TLR2 activation induced the expression of several PRRs on hepatic macrophages associated with the recognition of Lm and augmented macrophage bacterial clearance activity. Our findings provide insight into the intrinsic mechanisms of TLR2-induced Mo/MΦ migration and mobility, as well as the interaction between macrophages and hepatocytes in resistance to Lm infection.
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http://dx.doi.org/10.3389/fimmu.2019.01388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607897PMC
October 2020

Improved thermal stability of photoluminescence in CsPbBr microcrystals/CsPbBr nanocrystals.

J Colloid Interface Sci 2019 Oct 25;554:133-141. Epub 2019 Jun 25.

School of Science, Northeast Agricultural University, Harbin, Heilongjiang 150030, China.

Here, CsPbBr microcrystals (MCs) are synthesized using a two-phase liquid-liquid immiscible method. In order to unravel the bright green photoluminescence (PL) mechanism for in-situ CsPbBr MCs, the thermal stability of PL spectra for the supernatant and precipitate of reactants is investigated comparatively. Exciton binding energy, exciton-phonon (EP) coefficient and PL lifetime all indicate that the PL of the precipitate has similar temperature dependence as that of the supernatant. It is found that, according to its structural and optical characteristics, the supernatant of the reactants is CsPbBr nanocrystals (NCs). We also find that the bright green PL from the precipitate of the reactants is due to CsPbBr NCs embedded into CsPbBr MCs. Experimental results further reveal the size of CsPbBr NCs embedded into CsPbBr MCs is larger than that of CsPbBr NCs in the supernatant. The surface passivation of the composites can thus help to suppress the thermal quenching of PL for CsPbBr NCs, which opens a new avenue for enhancing the thermal stability of PL for perovskite NCs.
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http://dx.doi.org/10.1016/j.jcis.2019.06.083DOI Listing
October 2019

HCC-Derived Exosomes: Critical Player and Target for Cancer Immune Escape.

Cells 2019 06 8;8(6). Epub 2019 Jun 8.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China.

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver, and currently the second most common cause of cancer-related deaths worldwide with increasing incidence and poor prognosis. Exosomes are now considered as important mediators of host anti-tumor immune response as well as tumor cell immune escape. HCC-derived exosomes have been shown to attenuate the cytotoxicity of T-cells and NK cells, and promote the immuno-suppressive M2 macrophages, N2 neutrophils, and Bregs. These exosomes harbor several immune-related non-coding RNAs and proteins that drive immune-escape and tumor progression, and thus may serve as potential diagnostic biomarkers and therapeutic targets for HCC. In a previous study, we identified miR146a as an exosomal factor that promotes M2-polarization and suppresses the anti-HCC function of T-cells. In this review, we summarized the role of tumor-derived exosomes and their key components in mediating tumor immune escape during HCC development.
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http://dx.doi.org/10.3390/cells8060558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627799PMC
June 2019

SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC.

Oncoimmunology 2019;8(7):1601479. Epub 2019 Apr 17.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.

Emerging evidence indicates that cancer cell-derived exosomes contribute to cancer progression through the modulation of tumor microenvironment, but the underlying mechanisms are not fully elucidated. Here, we reported that hepatocellular carcinoma (HCC)-derived exosomes could remodel macrophages by activating NF-κB signaling and inducing pro-inflammatory factors, and resulted in M2-polarized tumor-associated macrophages. In addition, the expression of IFN-γ and TNF-α was inhibited, while the expression of inhibitory receptors such as PD-1 and CTLA-4 was upregulated in T cells by HCC-derived exosome educated macrophages. Data also revealed that HCC exosomes were enriched with miR-146a-5p and promoted M2-polarization. Further investigation demonstrated that the transcription factor Sal-like protein-4 (SALL4) was critical for regulating miR-146a-5p in HCC exosomes and M2-polarization. Mechanistically, SALL4 could bind to the promoter of miR-146a-5p, and directly controlled its expression in exosomes. Blocking the SALL4/miR-146a-5p interaction in HCC reduced the expression of inhibitory receptors on T cells, reversed T cell exhaustion, and delayed HCC progression in DEN/CCL-induced HCC mice. In conclusion, identification of a role of the exosomal SALL4/miR-146a-5p regulatory axis in M2-polarization as well as HCC progression provides potential targets for therapeutic and diagnostic applications in liver cancer.
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http://dx.doi.org/10.1080/2162402X.2019.1601479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527304PMC
April 2019

STAT3 directly regulates NKp46 transcription in NK cells of HBeAg-negative CHB patients.

J Leukoc Biol 2019 10 27;106(4):987-996. Epub 2019 May 27.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China.

NK cells play an important role in early control of HBV infection. The function of NK cells is inhibited in chronic hepatitis B virus (CHB) infection, although the underlying mechanism remains unknown. We found that the expression of STAT3 decreased in peripheral NK cells of CHB patients, and was associated with low levels of degranulation and IFN-γ secretion. In addition, STAT3 levels were positively correlated with cytolysis-associated molecules and antiviral cytokines, such as CD107a, granzyme B, perforin, and IFN-γ. HBsAg directly inhibited the expression and activation of STAT3 in NK cells, and knocking down STAT3 expression in NK cells inhibited proliferation, decreased cyclin d1 levels, and suppressed responsiveness to IL-21 stimulation. Furthermore, STAT3 directly bound to the promoter of NKp46, an important activating receptor of NK cells, to regulate its transcription and expression. Taken together, our findings indicate that STAT3 is an important positive regulator of NK cells, and provide a new mechanism of NK cell dysfunction in CHB.
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http://dx.doi.org/10.1002/JLB.2A1118-421RDOI Listing
October 2019

MMP-2-Controlled Transforming Micelles for Heterogeneic Targeting and Programmable Cancer Therapy.

Theranostics 2019 28;9(6):1728-1740. Epub 2019 Feb 28.

CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China.

Herein, through the active-peptide-functionalization, we developed a nanoscale micelles system (named HEKM) which consists of tumor microenvironment-regulated shape-changing with specific recognition abilities for enhanced cellular targeting, internalization and therapy of heterogeneic tumors. As a result, HEKMs could recognize and bind the tumor heterogeneity marker EGFR-HER2 complex, which led to an enhanced tumor targeting effect. In particular, HEKMs could self-assemble into nanorods under normal physiological conditions while transform into nanospheres in the tumor extracellular microenvironment by a sensitive response to matrix metalloproteinase-2 (MMP-2). The nanorods could prolong the blood circulation time while the nanospheres could accelerate tissue penetration in tumors. dual-modal targeted imaging was realized by FRET-fluorophore conjugation and gadolinium loading in HEKMs. Tumor cell apoptosis was achieved by proapoptotic element integration. The and studies both demonstrated that these rationally designed, shape-changing and targeting micelles could achieve maximized drug efficacy and minimum side effects.
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http://dx.doi.org/10.7150/thno.30915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485184PMC
March 2020

5'-triphosphate siRNA targeting HBx elicits a potent anti-HBV immune response in pAAV-HBV transfected mice.

Antiviral Res 2019 01 15;161:36-45. Epub 2018 Nov 15.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China. Electronic address:

RNA with 5'-triphosphate (3p-RNA) is recognized by RNA sensor RIG-I (retinoic acid-inducible gene I protein). Previously, we reported that small interfering RNA targeting HBx (3p-siHBx) could confer potent anti-hepatitis B virus (HBV) efficacy via HBx silencing and RIG-I activation. However, the characteristics of innate and adaptive immunity especially exhaustion profiles in the liver microenvironment in response to 3p-siHBx therapy have not been fully elucidated. Here, we observed that 3p-siHBx more significantly inhibited HBV replication in vivo. 3p-siHBx enhanced natural killer (NK) cell activation with KLRG1 and CD69 upregulation and interferon (IFN)-γ secretion. 3p-siHBx significantly reversed the exhaustion phenotype of CD8 T cells, and augmented CD8 T cell activation and function. Importantly, 3p-siHBx disrupted the differentiation of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), accompanied by the reduction of the immunosuppressive cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β. 3p-siHBx also enhanced dendritic cell maturation. Further investigation showed that RIG-I was involved in 3p-siHBx-induced IFN-α, IFN-β, and IFN-λ production. Moreover, RIG-I activation in HBV hepatocytes would improve the recruitment of CD8 T cells and NK cells. These results reveal that 3p-siHBx therapy can improve the immune microenvironment in HBV-carrier liver and inhibit HBV replication, indicating the potential utility of RIG-I ligands as molecular adjuvants for viral vaccines or candidate drugs.
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http://dx.doi.org/10.1016/j.antiviral.2018.11.006DOI Listing
January 2019

Inhibiting TrxR suppresses liver cancer by inducing apoptosis and eliciting potent antitumor immunity.

Oncol Rep 2018 Dec 27;40(6):3447-3457. Epub 2018 Sep 27.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China.

Liver cancer is one of the most common malignant tumors worldwide. Thioredoxin reductase (TrxR) is highly expressed in liver cancer cells. The present study aimed to investigate the effect of inhibiting TrxR on liver cancer and to better understand the underlying molecular and immuno-logical mechanisms associated with inhibition. It was demonstrated that targeting TrxR inhibited the growth and induced apoptosis of liver cancer cells, which was accompanied by activation of the mitogen associated protein kinase pathway. This inhibition was dependent on the production of reactive oxygen species (ROS). Blockage of ROS production reversed TrxR inhibitor‑induced antitumor effects. Blocking the Trx/TrxR system activated the mammalian target of rapamycin pathway and inhibited autophagy, which occurred in a ROS‑independent manner. TrxR inhibition led to lesions in the mitochondrial membrane, indicated by alterations in membrane potential. Mouse xenograft experiments were highly consistent with in vitro studies. Most importantly, blocking the Trx/TrxR system improved the tumor immune microenvironment. Together, these data demonstrated that TrxR is a potential target for liver cancer therapy, which could inhibit hepatocarcinogenesis and progression, and improve the antitumor immune response.
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http://dx.doi.org/10.3892/or.2018.6740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196602PMC
December 2018

Ultrafast spectroscopic studies of composition-dependent near-infrared-emitting alloyed CdSeTe quantum dots.

Phys Chem Chem Phys 2018 Sep;20(36):23556-23563

School of Electronic Engineering, Heilongjiang University, Harbin, 150080, China.

In this study, optical and structural characterizations of near-infrared-emitting alloyed CdSeTe quantum dots (QDs) are measured after the dissolution in toluene. Luminescence spectra are obtained from alloyed CdSeTe QDs under 800 nm femtosecond laser excitation. With increasing pump fluence, the line width or full width at half maximum (FWHM) of photoluminescence (PL) spectrum becomes larger than 10 nm due to increasing temperature. Ultrafast spectroscopic properties of CdSeTe QDs are investigated by means of time-resolved PL, transient absorption (TA) and Z scan techniques. Moreover, open-aperture (OA) Z scan measurement is used to clarify the composition and pump fluence dependence of optical nonlinearity under femtosecond laser excitation. With increasing pump fluence, evolution from saturable absorption to reverse saturable absorption in CdSeTe QDs is observed. The transition process is analyzed via a phenomenological model based on nonlinear absorption coefficient and saturation intensity, which indicates that CdSeTe QDs have potential for applications in all-optical switching devices.
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http://dx.doi.org/10.1039/c8cp03904fDOI Listing
September 2018

HMBOX1 in hepatocytes attenuates LPS/D-GalN-induced liver injury by inhibiting macrophage infiltration and activation.

Mol Immunol 2018 09 20;101:303-311. Epub 2018 Jul 20.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, China. Electronic address:

The HMBOX1 (Homeobox Containing 1) gene was first isolated from the human pancreatic cDNA libraries and is widely expressed in many tissues. Previously, we detected high expression of HMBOX1 in the liver, but its function was unclear. In this study, hepatocyte-specific HMBOX1 knockout mice (Hm mice) were generated and used to characterize the function of HMBOX1 in the LPS/D-GalN-induced acute liver failure model. HMBOX1-knockout exhibits exacerbated liver injury induced by LPS/D-GalN, accompanied with high levels of inflammatory cytokines both in the liver and in circulation. Further investigation demonstrated that HMBOX1 negatively regulates NF-κB signal transduction. Therefore, HMBOX1-knockout in hepatocytes promotes CCL2 expression through the activation of NF-κB signaling, which enhanced the infiltration of macrophages into the liver. In addition, the decrease of HMBOX1 in hepatocytes promotes the activation of macrophages, upregulating CD80 and MHCⅡ, as well as inflammatory factors TNF-α and IL-6. Importantly, overexpression of HMBOX1 rescued liver injury in Hm mice. These findings indicate that HMBOX1 in hepatocytes acts as a key immunosuppressive factor for inflammation and plays a critical protective role in LPS/D-GalN-induced liver injury.
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http://dx.doi.org/10.1016/j.molimm.2018.07.021DOI Listing
September 2018

Homeobox containing 1 inhibits liver cancer progression by promoting autophagy as well as inhibiting stemness and immune escape.

Oncol Rep 2018 Sep 10;40(3):1657-1665. Epub 2018 Jul 10.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China.

Homeobox containing 1 (HMBOX1) is a novel transcription repressor that is significantly downregulated in human liver cancer tissues and cell lines, but the exact biological function of HMBOX1 in liver cancer is still unknown. We observed a negative association between HMBOX1 expression level and the clinical stages of liver cancer. HMBOX1 also increased the LC3 II/LC3 I ratio, the endogenous autophagy marker, and inhibited the p38/AKT/mTOR pathway. Furthermore, cancer stem cell specific genes, including CD133, KLF4, ESG1 and SOX2, were significantly downregulated upon HMBOX1 overexpression. Finally, the susceptibility of HepG2 cells to NK cell‑mediated cytolysis was increased by HMBOX1 overexpression and weakened by siRNA‑mediated inhibition of HMBOX1. All these findings indicated that HMBOX1 expression in hepatocytes could protect against the progression of liver cancer, and the underlying mechanisms may include promoting autophagy, inhibiting CSC phenotype and increasing the sensitivity of tumor cells to NK cell cytolysis. Therefore, HMBOX1 may be useful for developing new treatments for liver cancer.
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http://dx.doi.org/10.3892/or.2018.6551DOI Listing
September 2018

IFN-γ protects from apoptotic neutrophil-mediated tissue injury during acute Listeria monocytogenes infection.

Eur J Immunol 2018 09 25;48(9):1470-1480. Epub 2018 Jul 25.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China.

Listeria monocytogenes (LM) is a foodborne Gram-positive intracellular pathogen that can cause listeriosis in humans and animals. Although phagocytes are known to be involved in the response to this infection, the role of neutrophils is not entirely clear. Here, we have demonstrated that soon after LM infection, a large number of IFN-γ-producing neutrophils quickly accumulated in the spleen, blood, and peritoneal cavity. Both in vivo and in vitro experiments demonstrated that neutrophils were an important source of IFN-γ. IFN-γ played a critical protective role against acute LM infection, as demonstrated by the poor survival of Ifng mice. Moreover, IFN-γ promoted bacterial clearance by the neutrophils, thereby inhibiting LM-induced neutrophil apoptosis and spleen damage. In addition to this, IFN-γ could effectively drive macrophage-mediated phagocytosis of apoptotic neutrophils, which was accompanied with TGF-β secretion and was involved in protection against tissue injury. Importantly, by phagocytizing apoptotic neutrophils, macrophages obtained myeloperoxidase, an important bactericidal molecule only produced by neutrophils, which further promoted the antibacterial activity of macrophages. These findings demonstrate that neutrophils are an important source of IFN-γ at the early stage of LM infection, which is characterized by both LM elimination and tissue-protective effects.
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http://dx.doi.org/10.1002/eji.201847491DOI Listing
September 2018

Intestinal Lamina Propria CD4 T Cells Promote Bactericidal Activity of Macrophages via Galectin-9 and Tim-3 Interaction during Salmonella enterica Serovar Typhimurium Infection.

Infect Immun 2018 08 23;86(8). Epub 2018 Jul 23.

Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, China

The intestinal immune system is crucial for protection from pathogenic infection and maintenance of mucosal homeostasis. We studied the intestinal immune microenvironment in a serovar Typhimurium intestinal infection mouse model. Intestinal lamina propria macrophages are the main effector cells in innate resistance to intracellular microbial pathogens. We found that Typhimurium infection augmented Tim-3 expression on intestinal lamina propria CD4 T cells and enhanced galectin-9 expression on F4/80 CD11b macrophages. Moreover, CD4 T cells promoted the activation and bactericidal activity of intestinal F4/80 CD11b macrophages via the Tim-3/galectin-9 interaction during Typhimurium infection. Blocking the Tim-3/galectin-9 interaction with α-lactose significantly attenuated the bactericidal activity of intracellular Typhimurium by macrophages. Furthermore, the Tim-3/galectin-9 interaction promoted the formation and activation of inflammasomes, which led to caspase-1 cleavage and interleukin 1β (IL-1β) secretion. The secretion of active IL-1β further improved bactericidal activity of macrophages and galectin-9 expression on macrophages. These results demonstrated the critical role of the cross talk between CD4 T cells and macrophages, particularly the Tim-3/galectin-9 interaction, in antimicrobial immunity and the control of intestinal pathogenic infections.
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http://dx.doi.org/10.1128/IAI.00769-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056851PMC
August 2018

Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion.

Nat Commun 2018 03 28;9(1):1241. Epub 2018 Mar 28.

The CAS Key Laboratory of Innate Immunity and Chronic Disease and Institute of Immunology, School of Life Science and Medical Center, University of Science and Technology of China, Hefei, 230027, Anhui, China.

A chronic viral or tumor microenvironment can push T cells to exhaustion by promoting coinhibitory ligand expression. However, how host factors control coinhibitory ligand expression and whether viral infection breaks this control during tumor progress is unknown. Here we show a close negative correlation between SALL4 or PD-L1 and miR-200c in tumors from 98 patients with HBV-related hepatocellular carcinoma. SALL4 or PD-L1 expression correlates negatively with miR-200c expression, and patients with lower levels of SALL4 or PD-L1 and higher miR-200c survive longer. Moreover, over-expression of miR-200c antagonizes HBV-mediated PD-L1 expression by targeting 3'-UTR of CD274 (encoding PD-L1) directly, and reverses antiviral CD8 T cell exhaustion. MiR-200c transcription is inhibited by oncofetal protein SALL4, which is re-expressed through HBV-induced STAT3 activation in adulthood. We propose that an HBV-pSTAT3-SALL4-miR-200c axis regulates PD-L1. Therapeutic strategies to influence this axis might reverse virus-induced immune exhaustion.
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http://dx.doi.org/10.1038/s41467-018-03584-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871883PMC
March 2018

pH-Triggered Peptide Self-Assembly for Targeting Imaging and Therapy toward Angiogenesis with Enhanced Signals.

ACS Appl Mater Interfaces 2018 Mar 23;10(9):7871-7881. Epub 2018 Feb 23.

CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience , National Center for Nanoscience and Technology of China , Beijing 100190 , P. R. China.

Mild acidic environment and angiogenesis are two typical characteristics of tumor. The specific response toward both lower pH and angiogenesis may enhance the targeting ability both for drug and diagnostic probe delivery. Herein, we present a kind of dual responding self-assembled nanotransformation material that is tumor angiogenesis targeting and pH triggered based on amphiphilic conjugation between peptides (STP) and aromatic molecules (tetraphenylethylene (TPE)). The morphology of the self-assembled peptide conjugates is responsibly changed from nanoparticles in neutral condition to nanofibers in acidic condition, which "turn on" the in vivo targeting imaging and accelerate the efficient drug delivery and in vivo therapy. On the basis of the well-controlled nanotransformation both in vitro and in vivo, we envisioned the successful demonstration of the responding materials would open a new avenue in turn on targeting imaging diagnostics and specific cancer therapeutics.
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http://dx.doi.org/10.1021/acsami.8b00583DOI Listing
March 2018

Pim-3 enhances melanoma cell migration and invasion by promoting STAT3 phosphorylation.

Cancer Biol Ther 2018 03 25;19(3):160-168. Epub 2018 Jan 25.

a Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University , Jinan , Shandong , China.

Melanoma is the deadliest form of commonly encountered skin cancer, and has fast propagating and highly invasive characteristics. Pim-3, a highly expressed oncogene in melanoma, is a highly conserved serine/threonine kinase with various biological activities, such as proliferation-accelerating and anti-apoptosis effects on cancer progression. However, whether Pim-3 regulates melanoma metastasis has not been determined. Here, we constructed a Pim-3-silencing short hairpin RNA (sh-Pim-3), a TLR7-stimulating ssRNA and a dual-function vector containing a sh-Pim-3 and a ssRNA, and transfected them into the B16F10 melanoma cell line to investigate the effects of Pim-3 on migration and invasion in melanoma. We found that sh-Pim-3 inhibited B16F10 cell migration and invasion in vitro. In a tumor-bearing mouse model, sh-Pim-3 significantly downregulated pulmonary metastasis of B16F10 melanoma cell in vivo. Mechanistically, sh-Pim-3 inhibited metastasis by regulating the expression of genes related to epithelial-mesenchymal transition (EMT). Further study revealed that by promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), Pim-3 induced the expression of Slug, Snail, and ZEB1, which enhanced EMT-related changes and induced melanoma migration and invasion. Our study suggests that Pim-3 is a potential effective target for melanoma therapy.
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http://dx.doi.org/10.1080/15384047.2017.1414756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790343PMC
March 2018

Single dose HBsAg CS-γ-PGA nanogels induce potent protective immune responses against HBV infection.

Eur J Pharm Biopharm 2018 Mar 13;124:82-88. Epub 2017 Dec 13.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, China. Electronic address:

Hepatitis B virus (HBV) infection is a severe threat to public health, which can be prevented by prophylactic vaccination. Here, we tested nanogels carriers in the prophylactic effect of hepatitis B surface antigen (HBsAg) vaccine. HBsAg nanogels (Ng) were prepared using chitosan (CS) and poly-γ-glutamic acid (γ-PGA). Positively charged Ng (+) and negatively charged Ng (-) were prepared by adjusting the CS and γ-PGA proportion. Dendritic cells (DCs) maturation in mice immunized with HBsAg Ng (+) and HBsAg Ng (-) could be augmented in response to pAAV/HBV1.2 plasmid challenge. Single-dose immunization with HBsAg Ng (+) induced HBsAg specific-antibodies. HBsAg Ng (+) immunized mice cleared HBsAg and restored anti-HBs production after pAAV/HBV1.2 plasmid challenge. Single-dose HBsAg Ng (+) induced humoral and cellular immunity, and could induce effector memory T cells. Single-dose HBsAg Ng (-) favored the induction of cellular immunity, and induced central memory T cells and effector memory T cells. However, HBsAg elimination was similar between HBsAg Ng (+)- and HBsAg Ng (+) plus HBsAg Ng (-)-immunized mice. Zeta potential measurements showed that HBsAg Ng (+) were more stable than HBsAg Ng (-). Therefore, Ng (+) are desirable HBsAg prophylactic vaccine carriers, providing long-term protection against HBV, and are a good choice to study and apply weakly immunostimulatory antigens.
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http://dx.doi.org/10.1016/j.ejpb.2017.12.003DOI Listing
March 2018

STAT3-blocked whole-cell hepatoma vaccine induces cellular and humoral immune response against HCC.

J Exp Clin Cancer Res 2017 11 7;36(1):156. Epub 2017 Nov 7.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, 250012, China.

Background: Whole-cell tumor vaccines have shown much promise; however, only limited success has been achieved for the goal of eliciting robust tumor-specific T-cell responses.

Methods: Hepatocellular carcinoma (HCC) cells, H22 and Hepa1-6, were modified by blocking the STAT3 signaling pathway with a STAT3 decoy oligodeoxynucleotide, and the immunogenicity and possibility of using these cell lysates as a vaccine were evaluated.

Results: STAT3-blocked whole HCC cell lysates inhibited tumor growth and tumorigenesis, and prolonged the survival of tumor-bearing mice. In addition, STAT3-blocked whole HCC cell lysates stimulated the activation of T cells and natural killer (NK) cells, and enhanced the infiltration of cytotoxic CD8 T cells in the tumor tissues. In addition, the maturation of dendritic cells (DCs) was enhanced, which promoted the generation of immunological memory against HCC. Furthermore, secondary immune responses could be primed as soon as these immunized mice were challenged with HCC cells, accompanied by T cell and NK cell activation and infiltration. Additionally, immunization with this vaccine decreased the generation of Tregs and the production of TGF-β and IL-10. Importantly, STAT3-blocked whole HCC cell lysates prevented HCC-mediated exhaustion of T cells and NK cells, showing low expression of checkpoint molecules such as PD-1 and TIGIT on T cells and NK cells in the immunized mice.

Conclusions: The newly generated STAT3-blocked whole-cell HCC vaccine has potential for cancer cell vaccination.
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http://dx.doi.org/10.1186/s13046-017-0623-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688805PMC
November 2017

Wnt2b attenuates HSCs activation and liver fibrosis through negative regulating TLR4 signaling.

Sci Rep 2017 06 21;7(1):3952. Epub 2017 Jun 21.

Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Shandong, China.

The Wingless-type MMTV integration site family member 2b (Wnt2b) has been found to be a principal mediator of liver development and regeneration. However, the significance of Wnt2b in the pathogenesis of fibrosis-related liver diseases remains undefined. Here, we report that Wnt2b was highly expressed in the fibrotic liver tissues, exhibiting protective effects against activation of hepatic stellate cells (HSCs) and fibrosis progression. We identified a negative regulation of Wnt2b on the toll-like receptor 4 (TLR4) activation-mediated pro-fibrogenic effects. Wnt2b was shown not only to directly suppress LPS-induced HSCs activation, but also to inhibit TLR4-enhanced the sensitivity of HSCs to transforming growth factor beta (TGF-β). Mechanistic study showed that Wnt2b suppresses TLR4 signaling through inhibiting the expression of TLR4 as well as the activation of NF-κB and MAPKs. These findings provided new insights into the pathophysiology of liver fibrosis by characterizing Wnt2b as a novel endogenous suppressor of TLR4 signaling, maintaining tissue homeostasis during the early stage of hepatic fibrosis-associated liver diseases.
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http://dx.doi.org/10.1038/s41598-017-04374-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479809PMC
June 2017

TLR9 Regulates the NF-κB-NLRP3-IL-1β Pathway Negatively in -Induced NKG2D-Mediated Intestinal Inflammation.

J Immunol 2017 07 2;199(2):761-773. Epub 2017 Jun 2.

Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China; and

TLRs are key sensors for conserved bacterial molecules and play a critical role in host defense against invading pathogens. Although the roles of TLRs in defense against pathogen infection and in maintaining gut immune homeostasis have been studied, the precise functions of different TLRs in response to pathogen infection in the gut remain elusive. The present study investigated the role of TLR signaling in defense against the Gram-negative bacterial pathogen The results indicated that TLR9-deficient mice were more susceptible to infection compared with wild-type and TLR2- or TLR4-deficient mice, as indicated by more severe intestinal damage and the highest bacterial load. TLR9 deficiency in intestinal epithelial cells (IECs) augmented the activation of NF-κB and NLRP3 inflammasomes significantly, resulting in increased secretion of IL-1β. IL-1β increased the expression of NKG2D on intestinal intraepithelial lymphocytes and NKG2D ligands on IECs, resulting in higher susceptibility of IECs to cytotoxicity of intestinal intraepithelial lymphocytes and damage to the epithelial barrier. We proposed that TLR9 regulates the NF-κB-NLRP3-IL-1β pathway negatively in -induced NKG2D-mediated intestinal inflammation and plays a critical role in defense against infection and in the protection of intestinal integrity.
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http://dx.doi.org/10.4049/jimmunol.1601416DOI Listing
July 2017
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