COLLOIDS AND SURFACES B-BIOINTERFACES
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2016
·
IF 3.902
Lu Chen,Jun Lin,Juan Li,Xiaozhao Wang,Junjun Zhuang,Huiming Wang,Kui Cheng,Wenjian Weng
In this study, mineralized collagen (COL) coatings with controlled loading and release of bone morphogenetic protein (rhBMP-2) as well as enhanced osteogenic differentiation were successfully achieved via the spatially-control of hydroxypropyltrimethyl ammonium chloride chitosan (HACC) within the coatings. The distribution of HACC in the inner part (HACC-IN) or the outer part (HACC-OUT) of the coatings were adjusted by different potential values and negative/positive alternations during alternating potentials assisted electrochemical deposition (AP-ECD). It was found that rhBMP-2 loading capacity was remarkably enhanced with the increased incorporation of HACC due to their strong interaction, and the release behavior was also tuned by HACC location. In general, HACC-IN coatings showed a prominent improvement in cytocompatibility and osteogenic differentiation. The main reason is considered that the inner location of HACC can eliminate the negative effect of HACC to initial cellular adhesion and bring to a sustained rhBMP-2 release behavior due to kinetic modification. An optimized coating in this work could load as high as 4644 ng/cm 2 rhBMP-2 and release only 25% for 14 days, which consequently leads to a better osteogenic differentiation. This study has thus inspired another promising protocol for designing growth factor incorporated bioactive coatings for bone implants with improved osteointegration.
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ADSORPTION SCIENCE & TECHNOLOGY
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2019
·
IF 1.2
Yue Sun,Weisheng Zheng,Deqiang Yin
Two novel weakly basic anion exchange resins BNH and BN2 bearing two different functional groups was fabricated via the two-step amination of chloromethylated polystyrene-divinylbenzene beads with dibutylamine and dimethylamine. The adsorption properties of BNH and BN2 for the 2-naphthalenesulfonic acid (NSA) removal from wastewater were compared with two synthesized monofunctional anion exchange resins BN0 and BN6 (derived from dimethylamine and dibutylamine, respectively). The experimental data revealed that the adsorption process on the four resins fitted well with the pseudo-second-order kinetics equation and the equilibrium isotherms were in good agreement with the Langmuir model. Thermodynamic analyses illustrated that 2-naphthalenesulfonic acid adsorption onto resins was an endothermic and spontaneous process. Importantly, BN2 still displayed relatively high adsorption capacity in the existence of Na2SO4, indicative of an excellent selectivity for 2-naphthalenesulfonic acid over sulfate than other resins. The obtained results elucidate that BN2 could have potential industrial application in effluent disposal fields because of its superior selectivity, acceptable kinetics, and desorption capability.
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OncoTargets and Therapy
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2019
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IF 3.046
Xiaolin Pu,Changqing Dong,Wenyu Zhu,Wei Li,Hua Jiang
Purpose Toll-like receptor 4 (TLR4) is involved in the inflammation in liver cancer. High-expressed stomatin-like protein 2 (SLP-2) is commonly reported in many cancer types. This study aims to investigate the functions of SLP-2 in TLR4-mediated inflammatory responses and tumor progression of liver cancer. Patients and methods Plasmid transfection technique was applied to silence and overexpress genes. Changes in cell viability and apoptosis were determined by performing cell counting kit-8 assay and flow cytometry. The levels of pro-inflammatory cytokines were determined by ELISA. We further measured the several types of the malignant transformation of SK-Hep1 cells to assess the effects of SLP-2 silencing on the cell migration and invasion, proliferation and angiogenesis of liver cancer in vitro. Western blot and RT-qPCR were performed for expression analysis. Results Lipopolysaccharide (LPS) promoted the cell proliferation of SK-Hep1 and production of tumor necrosis factor-α (TNF-α) and IL-6. SLP-2 silencing could inhibit the protein and mRNA levels of CD14 and Cdc42 and subsequently inhibited the levels of TNF-α and IL-6. Overexpressed CD14 not only remarkably reversed the proapoptotic ability of SLP-2 silencing and promoted the expression of Cdc42 and production of TNF-α and IL-6, but also notably reversed the inhibitory effects on the malignant abilities of SK-Hep1 cells by SLP-2 silencing. Conclusion SLP-2 silencing could significantly attenuate the inflammatory responses and tumor progression of liver cancer via inhibiting LPS/TLR4 signal transduction through the repression of CD14.
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Acta Pharmaceutica Sinica B
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2019
·
IF 5.808
Yahui Huang,Shuqiang Chen,Shanchao Wu,Guoqiang Dong,Chunquan Sheng
A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o .) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.
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Journal of Materials Chemistry B
·
2023
·
IF 7
Yanhao Zhang,Ji Wang,Hanlei Xing,Chao Liu,Wenhui Zha,Shuo Dong,Yuhao Jiang,Xinsong Li
mRNA vaccines have emerged as a highly promising approach for preventing cancer and infectious diseases, attributed to their superior immunogenicity, rapid development speed, and quality-controlled scale production. While homologous mRNA vaccine administration is currently the most prevalent method employed in clinical settings, heterologous administration is a promising avenue worth exploring. In this report, two types of mRNA vaccine formulations for SARS-CoV-2 infection were developed based on different lipid nanoparticle (LNP) delivery systems, and heterologous and homologous mRNA vaccinations were administered to explore the levels of immune responses comparatively. First, five novel H-series ionizable lipids were synthesized and confirmed by NMR and MS. Subsequently, six SARS-CoV-2 receptor-binding domain (RBD) mRNA-encapsulated LNP formulations were prepared using a microfluidic mixer based on H-series and MC3 lipids. These formulations exhibited spherical structures with an average diameter ranging from 90–140 nm, as characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The safety of these formulations was confirmed in vitro by the cytotoxicity assay. Moreover, transfection assay, lysosomal escape test, and western blot, and in vivo biodistribution analyses collectively demonstrated that lipids H03 and MC3 exhibited superior in vitro and in vivo delivery efficacy in comparison to other H-series lipids. Notably, H03-Fluc mRNA exhibited an approximately 2.2-fold higher in vivo bioluminescence signal intensity than MC3-Fluc mRNA. Additionally, evaluation of humoral immunity demonstrated that homologous H03-mRNA vaccination elicited an immune response that was approximately 3-fold higher than that of homologous MC3-mRNA vaccination. More significantly, the heterologous H03-mRNA/MC3-mRNA vaccination elicited an immune response that was approximately 2-3-fold higher than that of homologous H03-mRNA vaccination and 6–9-fold higher than that of homologous MC3-mRNA vaccination, without any observable adverse effects. These results suggest that heterologous mRNA vaccination is superior to homologous mRNA vaccination and may be attributed to differences in LNP carriers. Therefore, our research may inspire further exploration of different delivery systems to enhance mRNA-based therapeutics.
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JOURNAL OF NEUROSCIENCE
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2021
·Vol. 41
·期 23
·4976-4990
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IF 6.167
Jinxing Hou,Huiru Bi,Zhuoyang Ye,Wenhui Huang,Gang Zou,Xiaochuan Zou,Yun Stone Shi,Ying Shen,Quanhong Ma,Frank Kirchhoff,Yimin Hu,Guiquan Chen
Mutations on γ-secretase subunits are associated with neurologic diseases. Whereas the role of γ-secretase in neurogenesis has been intensively studied, little is known about its role in astrogliogenesis. Recent evidence has demonstrated that astrocytes can be generated from oligodendrocyte precursor cells (OPCs). However, it is not well understood what mechanism may control OPCs to differentiate into astrocytes. To address the above questions, we generated two independent lines of oligodendrocyte lineage-specific presenilin enhancer 2 (Pen-2) conditional KO mice. Both male and female mice were used. Here we demonstrate that conditional inactivation of Pen-2 mediated by Olig1-Cre or NG2-CreERT2 causes enhanced generation of astrocytes. Lineage-tracing experiments indicate that abnormally generated astrocytes are derived from Cre-expressing OPCs in the CNS in Pen-2 conditional KO mice. Mechanistic analysis reveals that deletion of Pen-2 inhibits the Notch signaling to upregulate signal transducer and activator of transcription 3, which triggers activation of GFAP to promote astrocyte differentiation. Together, these novel findings indicate that Pen-2 regulates the specification of astrocytes from OPCs through the signal transducer and activator of transcription 3 signaling.SIGNIFICANCE STATEMENT Astrocytes and oligodendrocyte (OLs) play critical roles in the brain. Recent evidence has demonstrated that astrocytes can be generated from OL precursor cells (OPCs). However, it remains poorly understood what mechanism governs the differentiation of OPCs into astrocytes. In this study, we took advantage of OL lineage cells specific presenilin enhancer 2 (Pen-2) conditional KO mice. We show that deletion of Pen-2 leads to dramatically enhanced astrocyte differentiation from OPCs in the CNS. Mechanistic analysis reveals that deletion of Pen-2 inhibits Hes1 and activates signal transducer and activator of transcription 3 to trigger GFAP activation which promotes astrocyte differentiation. Overall, this study identifies a novel function of Pen-2 in astrogliogenesis from OPCs.
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FOOD AND CHEMICAL TOXICOLOGY
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2014
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IF 2.61
Jingze Duan,Yan Xie,Huilin Luo,Guowen Li,Tao Wu,Tong Zhang
Flavonoid isorhamnetin occurs in various plants and herbs, and demonstrates various biological effects in humans. This work will clarify the isorhamnetin absorption mechanism using the Caco-2 monolayer cell model. The isorhamnetin transport characteristics at different concentrations, pHs, temperatures, tight junctions and potential transporters were systemically investigated. Isorhamnetin was poorly absorbed by both passive diffusion and active transport mechanisms. Both trans- and paracellular pathways were involved during isorhamnetin transport. Active transport under an ATP-dependent transport mechanism was mediated by the organic anion transporting peptide (OATP); isorhamnetin’s permeability from the apical to the basolateral side significantly decreased after estrone-3-sulfate was added ( p < 0.01). Efflux transporters, P-glycoproteins (P-gp), breast cancer resistance proteins (BCRP) and multidrug resistance proteins (MRPs) participated in the isorhamnetin transport process. Among them, the MRPs (especially MRP2) were the main efflux transporters for isorhamnetin; transport from the apical to the basolateral side increased 10.8-fold after adding an MRP inhibitor (MK571). This study details isorhamnetin’s cellular transport and elaborates isorhamnetin’s absorption mechanisms to provide a foundation for further studies.
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Journal of Biomedical Nanotechnology
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2022
·Vol. 18
·期 11
·2470-2478
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IF 3.641
Tu Rong,You Xiaoguang,Ding Zhichao,Wu Huanyu,Zhao Linlu,Qiu Zhi,Wei Junjie,Yang Xiaofeng
Development of imaging methods that can detect target molecules will be of great significance for non-invasive molecular diagnosis. Vascular endothelial growth factor receptor-2 (VEGFR-2) is a broadly expressed target, and VEGFR-2-specific agents have been used in biological therapy.
In this study, amine-reactive coupling was used to label the polypeptide VEGF125–136 with a Gd(DOTA) complex to create a magnetic resonance contrast agent, VEGF125–136-Gd, which binds to VEGFR-2. Using T1-weighted magnetic resonance imaging, we explored the tumor cell-targeting
ability of VEGF125–136-Gd and its enhancement of T1-weighted image intensity using human hepatoma (HepG2) cells and found that the signal-to-noise ratio (SNR) increased commensurately with the concentration of VEGF125–136-Gd. At a concentration of 2 mM, the SNR produced by VEGF125–136-Gd
was 5.4-fold higher than that produced by a Gd-labelled non-targeting polypeptide (NTPP-Gd) control. We also evaluated the tumor-targeting efficiency of VEGF125–136-Gd in nude mice injected with human hepatoma (HepG2) cells. Preliminary in vivo imaging of VEGFR-2 in tumor tissue
revealed a targeting peak 60 min post administration of VEGF125–136-Gd, the intensity of which was 23% higher than the SNR of NTPP-Gd at the same time point. Our findings may help lay the foundation for clinical applications of VEGF125–136-Gd in targeted imaging.
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JOURNAL OF INFECTIOUS DISEASES
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2008
·Vol. 197
·期 1
·117-125
·
IF 6.035
Michaëlsson Jakob,Long Brian R.,Loo Christopher P.,Lanier Lewis L.,Spotts Gerald,Hecht Frederick M.,Nixon Douglas F.
Natural killer (NK) cells are believed to play a role in human immunodeficiency virus type 1 (HIV-1) disease progression, and NK cell levels are reduced in individuals with chronic HIV-1 infection. Interleukin (IL)-2 therapy results in an expansion of CD4+ T cells as well as NK cells; however, little is known about the detailed effects of IL-2 therapy on NKcells in HIV-1 infection in general and in early infection in particular. Here, we investigated the effects of combined IL-2 therapy and antiretroviral therapy (ART) on the number, frequency, phenotype, and interferon (IFN)-γ production of NK cells in individuals with early HIV-1 infection. Patients randomized to receive combined ART and IL-2 therapy predominantly expanded CD56dim NK cells, and the expansion was greater than in patients randomized to receive ART alone. Importantly, NK cell receptor expression and IFN-γ production were maintained over time. This reconstitution ofNKcells may be useful in helping contain viremia if patients discontinue therapy or develop drug resistance.
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Frontiers in Pharmacology
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2022
·
IF 5.988
Wu Meng,Cui Jingyi,Hou Huimin,Li Ying,Liu Shengjie,Wan Li,Zhang Lili,Huang Wei,Sun Gaoyuan,Liu Jingchao,Jin Pengfei,He Shunmin,Liu Ming
Background: The inactivation of tumor-suppressor p53 plays an important role in second generation anti-androgens (SGAs) drug resistance and neuroendocrine differentiation in castration-resistant prostate cancer (CRPC). The reactivation of p53 by blocking the MDM2–p53 interaction represents an attractive therapeutic remedy in cancers with wild-type or functional p53. Whether MDM2-p53 inhibitor could overcome SGAs drug resistance in CRPC is still needed further research. Here, we investigated the anti-tumor efficacy and mechanisms of a novel MDM2-p53 inhibitor XR-2 in CRPC.Methods: To investigate the functions and mechanisms of XR-2 in prostate cancer, in vitro and in vivo biofunctional assays were performed. Western blot and qRT-PCR assay were performed to detect the protein and mRNA expression levels of indicated genes. CCK8, colony formation, flow cytometry and senescence assays were performed for cell function identifications. RNA-sequencing and bioinformatics analysis were mainly used to identify the influence of XR-2 on prostate cancer cells transcriptome. Subcutaneous 22Rv1 derived xenografts mice model was used to investigate the in vivo anti-tumor activity of XR-2. In addition, the broad-spectrum anti-tumor activities in vivo of XR-2 were evaluated by different xenografts mice models.Results: XR-2 could directly bind to MDM2, potently reactivate the p53 pathway and thus induce cell cycle arrest and apoptosis in wild-type p53 CRPC cell lines. XR-2 also suppresses the AR pathway as p53 regulates AR transcription inhibition and MDM2 participates in AR degradation. As a result, XR-2 efficiently inhibited CRPC cell viability, showed a synergistic effect with enzalutamide and overcame enzalutamide resistance both in vitro and in vivo. Moreover, results illustrated that XR-2 possesses broad-spectrum anti-tumor activities in vivo with favourable safety.Conclusion: MDM2-p53 inhibitor (XR-2) possesses potently prostate cancer progresses inhibition activity both in vitro and in vivo. XR-2 shows a synergistic effect with enzalutamide and overcomes enzalutamide resistance.
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NANOTECHNOLOGY
·
2021
·Vol. 32
·期 42
·425101
·
IF 3.874
Qing Zhang,Lian Wu,Shaozheng Liu,Qingjie Chen,Lingpeng Zeng,Xuezhong Chen,Qing Zhang
Photodynamic therapy (PDT) and immunotherapy have been often adopted for ovarian cancer therapy, yet their application is limited by the high recurrence rate and toxic side effects. Intriguingly, nanoparticles contribute to enhancing the performance of PDT. Here, we investigated the synthesis of HER-2-Nanobody (Nb)-conjugated human serum albumin (HSA) incorporated with chlorin (Ce6) and catalase (CAT) (Nb@HCC), and analyzed the synergic effect of Nb@HCC-mediated PDT and immunotherapy for SK-OV-3 tumors. The Ce6 and CAT were incorporated into HSA to construct the HCC nanoparticles. HER-2-Nanobody was the purified bacterial crude extract, and conjugated with HCC to prepare Nb@HCC via heterodisulfide. The effects of Nb@HCC with near infrared ray (NIR) irradiation on moderating hypoxia and hypoxia inducible factor-1α (HIF-1α) expression were evaluated in the SK-OV-3 cells and tumor tissues. A SK-OV-3 tumor-bearing model was developed, where the synergistic effect of Nb@HCC-mediated PDT and anti-CTLA-4 therapy was investigated. Nb@HCC with a 660 nm laser irradiation could induce massive reactive oxygen species and trigger apoptosis in SK-OV-3 cells. Nb@HCC and PDT promoted danger-associated molecular patterns (DAMPs), which indicated immunogenic cell death and maturation of dendritic cells in the SK-OV-3 cells. Irradiated by NIR, Nb@HCC alleviated the hypoxia and decreased the expression of HIF-1α. The Nb@HCC-mediated PDT and anti-CTLA-4 therapy synergically inhibited the progression of distant tumor, and induced T cell infiltration. Biosafety tests suggested that Nb@HCC would not cause damage to the major organs with less toxicity and side effects. To conclude, a combination of Nb@HCC-mediated PDT and anti-CTLA-4 therapy could inhibit the progression of distant tumor to attain remarkable therapeutic outcomes.
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PHYTOTHERAPY RESEARCH
·
2026
·
IF 8.1
Huaiying Tang,Qin Xiang,Yue Zhang,Yu Zhang,Xiangxiang Fu,Liming Tan,Yongli Zhang,Siqi Li,Dong Gong,Xu Guo,Yonghong Zhang,Li Chen,Tao Zheng,Qibin Wang
Type 2 diabetes mellitus (T2DM) is frequently accompanied by chronic ethanol (ET) consumption, which worsens metabolic dysregulation and organ damage. Cinnamic acid (CA), a natural compound with anti-diabetic and hepatoprotective effects, shows therapeutic potential, but its role in mitigating ET-exacerbated hepatocyte injury in diabetes remains unclear. This study thus investigated whether CA protects against ET-induced hepatocyte pyroptosis under diabetic conditions and explored the underlying mechanisms. In vitro, HepG2 cells cultured under high-glucose (HG) conditions were exposed to ET to simulate a diabetic state with concomitant alcohol intake. Pyroptosis was evaluated by morphological examination and annexin V/PI staining. The involvement of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3)/gasdermin D (GSDMD) pathway and AMP-activated protein kinase (AMPK) activation was assessed via immunoblotting, reactive oxygen species (ROS) detection, and molecular docking. In vivo, a T2DM mouse model was established using a high-fat diet combined with streptozotocin injection, followed by ET exposure and CA treatment. Metabolic parameters, histopathological changes, and hepatic signaling pathways were analyzed. Our results showed that ET exposure significantly increased pyroptotic body formation, ROS production, and NLRP3/GSDMD pathway activation in HG-treated HepG2 cells—all of which were reversed by CA in a concentration-dependent manner. Mechanistically, CA directly bound to and activated AMPK, and the protective effects were abolished by the AMPK inhibitor Compound C. In T2DM mice, ET exposure aggravated insulin resistance, dyslipidemia, hepatic steatosis, and histopathological abnormalities, whereas CA intervention ameliorated these adverse effects and modulated the AMPK-NLRP3/GSDMD signaling axis in liver tissue. Collectively, these findings demonstrate that CA alleviates ET-exacerbated hepatocyte pyroptosis under diabetic conditions by activating AMPK and subsequently inhibiting the NLRP3/GSDMD signaling cascade. This study provides novel insights into the therapeutic potential of CA in T2DM complicated by alcoholic hepatocellular injury.
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