Zhenyu Li

Shandong University, Chi-nan-shih, Shandong Sheng, China

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Publications (59)142.64 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The effect of infusion of lentiviral vector‑mediated, genetically engineered dendritic cells (DCs) following allogeneic bone marrow transplantation (allo‑BMT) on graft‑versus‑host disease (GVHD) and graft‑versus‑leukemia (GVL) was investigated in a mouse model. Lentivirus‑mediated expression of soluble tumor necrosis factor receptor 1 (sTNFR1) converted immature DCs (imDCs) from BABL/c mice into engineered DCs in vitro. An EL4 leukemia allo‑BMT model of BABL/c to C57BL/6 mice was established. Engineered DCs with donor bone marrow cells and splenocytes were subsequently transplanted into myeloablatively irradiated recipients. The average survival duration in the sTNFR1‑ and pXZ9‑imDC groups was significantly prolonged compared with that of the allo‑BMT group (P<0.05). Mild histological changes in GVHD or leukemia were observed in the recipients in the sTNFR1‑imDC group and clinical GVHD scores in this group were significantly decreased compared with those of the transplantation and pXZ9‑imDC groups. Serum interferon‑γ levels were decreased in the pXZ9‑imDC and sTNFR1‑imDC groups compared with those in the allo‑BMT group (P<0.05), with the reduction being more significant in the sTNFR1‑imDC group (P<0.05). Serum interleukin‑4 expression levels were decreased in the allo‑BMT group, but gradually increased in the pXZ9‑imDC and sTNFR1‑imDC groups (P<0.05). Co‑injection of donor genetically‑engineered imDCs was able to efficiently protect recipient mice from lethal GVHD while preserving GVL effects during allo‑BMT.
    Molecular Medicine Reports 12/2014; · 1.17 Impact Factor
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    ABSTRACT: Mesenchymal stem cells (MSCs) are a promising candidate for cellular therapies. Co-transplantation of MSCs and hematopoietic stem cells (HSCs) promotes successful engraftment and improves hematopoietic recovery. In this study, the effects of co-transplantation of HSCs and mouse bone marrow (BM)-derived MSCs overexpressing CXCR4 (CXCR4-MSC) on CXCR4-MSC homing capacity and the reconstitution potential in lethally irradiated mice were evaluated. Recovery of donor-derived peripheral blood leukocytes and platelets was accelerated when CXCR4-MSCs were co-transplanted with BM cells. The frequency of c-kit(+)Sca(+)Lin(-) HSCs was higher in recipient BM following co-transplantation of CXCR4-MSCs compared with the EGFP-MSC control and the BMT only groups. Surprisingly, the rate of early engraftment of donor-derived BM cells in recipients co-transplanted with CXCR4-MSCs was slightly lower than in the absence of MSCs on day 7. Moreover, co-transplantation of CXCR4-MSCs regulated the balance of T helper cells subsets. Hematopoietic tissue reconstitution was evaluated by histopathological analysis of BM and spleen. Co-transplantation of CXCR4-MSCs was shown to promote the recovery of hematopoietic organs. These findings indicate that co-transplantation of CXCR4-MSCs promotes the early phase of hematopoietic recovery and sustained hematopoiesis.
    Cell biochemistry and biophysics. 11/2014;
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    ABSTRACT: To investigate the effect of the lentiviral vector mediated CXCR4 overexpressed mesenchymal stem cell (MSCs) on graft-versus-host disease (GVHD).
    10/2014; 35(10):936-40.
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    ABSTRACT: Compared to 17-AAG, 7h29 exhibited lower hepatotoxicity in mice, higher Hsp90 inhibitory activity in vitro and antitumor activity in human breast carcinoma (MDA-MB-231) xenograft nude mice.
    European Journal of Medicinal Chemistry. 09/2014; 87:346–363.
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    ABSTRACT: DNA topoisomerase II (Topo II) is an essential nuclear enzyme and a validated target for anticancer agent screening. CS1, a novel 2-phenylnaphthalene, had potent cytotoxicity against nine tested tumor cell lines and showed 6–10-fold less toxicity against normal cell lines compared with etoposide. In addition, CS1 showed potential anti-multidrug resistance capabilities. kDNA decatenation, DNA relaxation and cleavage complex assay indicate that CS1 works as an nonintercalating topoisomerase IIα (Topo IIα) inhibitor by stabilizing the DNA-Topo IIα cleavage complex. CS1 also induced DNA breaks in cells evidenced by comet tails in MDA-MB-231 cells and accumulation of γH2AX foci. The ability of CS1 in inducing DNA breaks mediated by Topo II resulted in G2/M phase arrest and apoptosis. Moreover, CS1 exhibited dramatic in vivo antitumor activity and lower toxicity compared with etoposide. This work supports the development of CS1 as a promising candidate for treatment of cancer by targeting Topo IIα.
    Biochemical and Biophysical Research Communications 09/2014; · 2.28 Impact Factor
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    ABSTRACT: Forty eight 2-phenylnaphthalenoids were designed and successfully synthesized. Their in vitro cytotoxicities against the proliferations of MDA-MB-231, A549 and HeLa cell lines and inhibitory activities on DNA topoisomerase were evaluated. The quantitative structure-activity relationship (QSAR) studies were established on the basis of cytotoxicity data from MDA-MB-231 cell line. Among these compounds, compound 5 showed potent antiproliferative activity (IC50 = 1 μM) against MDA-MB-231 cells and inhibitory activity on topoisomeraseIIα. Further, in vivo antitumor study with xenograft nude mice indicated that compound 5 inhibited the growth of MDA-MB-231 cells and showed lower toxicity than etoposide (VP16). This work indicates that 2-phenylnaphthalenoids represent a novel type of TopoIIα-inhibitory scaffold for developing new antitumor chemotherapeutic agents.
    European Journal of Medicinal Chemistry 09/2014; 86C:782-796. · 3.43 Impact Factor
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    ABSTRACT: Astragali Radix (Huangqi), a well-known traditional Chinese medicinal plant, has been used for centuries as a reinforcing vital energy herb in China. In this study, the antifatigue effect of Astragali Radix was investigated by 1H NMR based metabolomic approach coupled with multivariate statistical analysis. The results indicated that oral administration of Astragali Radix at a dose of 3g/kg body weight could significantly prolong the exhaustive swimming time of rats, and alter the serum and urine metabolome. The rats treated by Astragali Radix extracts showed higher levels of glucose, creatine, glycine, citrate, guanidinoacetate, allantoin, dimethylglycine, dimethylamine (DMA), creatinine, betaine and malate and lower levels of lactate, choline species, O-acetylated glycoproteins (OAG), glycerol, β-OH-butyrate, α-ketoglutarate, trimethylamine (TMA) and hippurate. And these metabolic changes indicated that Astragali Radix facilitated recovery from fatigue by regulating the glycometabolism, lipid metabolism and energy metabolism. Chemical analysis showed that various components were present in the Astragali Radix extracts, the bioactive compounds responsible for the antifatigue activity should be further investigated.
    Molecular BioSystems 09/2014; · 3.35 Impact Factor
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    ABSTRACT: Thirty-three 17-arylmethylamine-substituted derivatives of geldanamycin (GA) were designed, synthesized and evaluated for the anti-proliferation activity on human cancer cell lines, LNCaP and MDA-MB-231. Three derivatives (22, 33 and 34) exhibited potent cytotoxicity with IC50 values range from 0.05 to 0.51 μM against both cell lines. Hepatotoxicity test in mice demonstrated that the levels of both AST and ALT of 34-treated group were lower than that of 17-AAG group. Western blot assay indicated that 34 was more potent than 17-AAG in the down-regulation of Hsp90 client proteins CDK4, Her2, EGFR and Raf. Moreover, 34 showed excellent in vivo antitumor activity in the MDA-MB-231 xenograft nude mice, which is superior to 22 and 33, and 17-AAG, indicating that 34 was a promising antitumor candidate. Additionally, preliminary structure-activity relationship (SAR) and molecular dynamics (MD) simulations of this new series of GA derivatives were also investigated, suggesting a theoretical model of 17-arylmethylamine geldanamycins binding to Hsp90.
    European journal of medicinal chemistry. 08/2014; 85C:359-370.
  • 07/2014; 35(7):661-663.
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    ABSTRACT: Twenty-six 17-phenylethylamine-modified geldanamycin derivatives were synthesized and evaluated for anti-proliferation activity in human cancer cell lines, LNCaP and MDA-MB-231. Five derivatives (2j, 2q, 2v, 2x and 2y) showed excellent in vitro antitumor activities. Among them, compound 2y was the most potent lead, with IC50 values of 0.27 ± 0.11 and 0.86 ± 0.23 μM for LNCaP and MDA-MB-231, respectively. In particular, compound 2y was more active than its precursor geldanamycin against LNCap cells. Liver injury test in mice demonstrated that 2y group showed no significant difference for serum alanine aminotransferase (ALT) activity versus vehicle control, indicating that 2y was a promising antitumor candidate. Preliminary structure-activity relationship (SAR) and molecular dynamics (MD) simulations of this new series of geldanamycin derivatives were also investigated, suggesting a theoretical model of 17-phenylethylaminegeldanamycins binding to Hsp90. This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 06/2014; · 2.47 Impact Factor
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    ABSTRACT: Graft-versus-host disease (GVHD) as a major complication after allogeneic hematopoietic stem cell transplantation is not well prevented now. We have observed that interleukin-22 (IL-22) produced by Th22, Th1, and Th17 cells participated in GVHD development in our previous study. However, the role of IL-22 in GVHD is still ambiguous. The aim of this study was to illuminate the pathological or protective function and the potential mechanism of IL-22 in the GVHD process. In the present study, we found that compared with mice cotransferred with bone marrow and spleen cells (BS mice) without IL-22 administration, more serious tissue damage and higher GVHD clinical score were observed in BS+IL-22 mice. IL-22 administration was a benefit to early recovery of thymus after irradiation-induced injury. Administration of IL-22 could promote Th1 and Tc1 cell expansion in mesenteric lymph nodes but reduce CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cell number. Levels of systemic inflammatory cytokines (IFN-γ and TNF-α) were upregulated, while the level of immunosuppressive cytokine IL-10 was downregulated in recipients with IL-22 injection. In conclusion, IL-22, which exacerbates both local immune responses and systemic inflammation of recipients, plays a pathogenic role in the GVHD process. The potential mechanism of IL-22 in GVHD may attribute to increased alloreactive effector Th1 and Tc1 cells and decreased inhibitory Treg cell.
    Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 04/2014; · 1.63 Impact Factor
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    ABSTRACT: As a continuation of our efforts to discover and develop back-up analogs of DAPYs, novel substituted nitropyridine derivatives were designed via a structure-based core refining approach, synthesized and evaluated for their in vitro HIV-1 activity in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against wild-type HIV-1 IIIB. Most notably, the compound 7b was identified as the most promising candidate in inhibiting HIV-1 replication with an EC50 value of 0.056 μM and a selective index (SI) of 1251, which were much better than those of NVP (EC50 = 0.23 μM) and DLV (EC50 = 0.51 μM). Some other compounds, 7k, 7c, 7j and 7e, were also endowed with a favorable anti-HIV-1 potency (EC50 = 0.034, 0.11, 0.11 and 0.16 μM, respectively). Some antivirally active compounds also showed moderate inhibitory activity against RT. Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogs provide valuable avenues for future molecular optimization.
    European Journal of Medicinal Chemistry 02/2014; 76C:531-538. · 3.43 Impact Factor
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    ABSTRACT: The analysis of genome sequence indicated that Streptomyces sp. LZ35 has the potential of producing many types of secondary metabolites, including p-terphenyls and geldanamycins. The fermentation of LZ35 in laboratory produces geldanamycins as the major components, which hampers the isolation of minor compounds. To clean the background of geldanamycins, the mutant strain LZ35ΔgdmAI of Streptomyces sp. LZ35 was constructed by disrupting the first PKS module of geldanamycin gene cluster (gdm). From this mutant, five novel p-terphenyls bearing glucuronic acid moiety, namely echosides A-E (1-5), were isolated with the aid of chromophore-guided fractionation. The structures of 1-5 were elucidated by the analysis of their HR-ESI-MS and NMR spectroscopic data. DNA relaxation assay indicated that compound 1 had evident inhibitory activity against topoisomerase I. Moreover, the inhibitory activity of compound 3 against topoisomerase IIα is approximately equal to VP16, indicating that p-terphenyl O-β-glucuronides are promising leads for the development of novel inhibitors of topoisomerases.
    Bioorganic & medicinal chemistry letters 01/2014; · 2.65 Impact Factor
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    ABSTRACT: A series of substituted nitropyridine derivatives were identified as potent HIV NNRTIs via a structure-based core refining approach.
    European Journal of Medicinal Chemistry. 01/2014; 76:531–538.
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    ABSTRACT: We evaluated the potential relationship between miRNAs and Th17 cytokines in multiple myeloma (MM) patients. Twenty-seven newly diagnosed myeloma patients and eight normal donors were studied. We determined that the relative expression levels of miR-15a/16, miR-34a, miR-194 in MM patients were significantly lower than those in the healthy controls with exception for miR-181a/b, which showed significantly higher in MM patients (P < 0.05). In contrast, the levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to healthy controls while IL-22 was down-regulated (P < 0.05). The expression patterns of them were differentially present in various groups according to the International Staging System (ISS) criteria. Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients. Establishment of the relationship may be useful for understanding the pathogenesis of MM and for clinical diagnosis of the disease.
    Leukemia Research. 01/2014;
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    ABSTRACT: The dried root of Polygala tenuifolia, named Radix Polygalae, is a well-known traditional Chinese medicine. Triterpenoid saponins are some of the most important components of Radix Polygalae extracts and are widely studied because of their valuable pharmacological properties. However, the relationship between gene expression and triterpenoid saponin biosynthesis in P. tenuifolia is unclear.
    PLoS ONE 01/2014; 9(8):e105765. · 3.53 Impact Factor
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    ABSTRACT: A series of novel N-arylmethyl substituted piperidine-linked aniline derivatives were designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells. All the new compounds showed moderate to potent activities against wild-type (wt) HIV-1 with an EC50 range from 0.022 to 2.1μM. Among them, compound 5a6 (EC50=0.022±0.0091μM, SI >10,770) was confirmed to be the most potent and selective inhibitor, which proved more potent than DDI and DLV in a cell-based assay against wt HIV-1, and more efficient than NVP in an RT (reverse transcriptase) assay. Besides, it is worth noting that compound 7a1 retained moderate inhibitory activity (EC50=4.8±0.95μM) against the HIV-1 double RT mutant strain (K103N/Y181C). The preliminary structure-activity relationship was discussed and rationalized by molecular simulation.
    Bioorganic & medicinal chemistry 11/2013; · 2.82 Impact Factor
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    ABSTRACT: Carbon tetrachloride (CCl4) is commonly used as a model toxicant to induce chronic and acute liver injuries. In this study, metabolite profiling and gene expression analysis of liver tissues were performed by nuclear magnetic resonance and quantitative real-time polymerase chain reaction to understand the responses of acute liver injury system in rats to CCl4. Acute liver injury was successfully induced by CCl4 as revealed by histopathological results and significant increase in alanine aminotransferase and serum aspartate aminotransferase. We found that CCl4 caused a significant increase in lactate, succinate, citrate, dimethylgycine, choline and taurine. CCl4 also caused a decrease in some of the amino acids such as leucine/isoleucine, glutamine/glutathione and betaine. Gene function analysis revealed that 10 relevant enzyme genes exhibited changes in expressions in the acute liver injury model. In conclusion, the metabolic pathways, including tricarboxylic acid cycle, antioxidant defense systems, fatty acid β-oxidation, glycolysis and choline and mevalonate metabolisms were impaired in CCl4-treated rat livers. These findings provided an overview of the biochemical consequences of CCl4 exposure and comprehensive insights into the metabolic aspects of CCl4-induced hepatotoxicity in rats. These findings may also provide reference of the mechanisms of acute liver injury that could be used to study the changes in functional genes and metabolites.
    Journal of pharmaceutical and biomedical analysis 10/2013; 89C:42-49. · 2.45 Impact Factor
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    ABSTRACT: Twelve new aryl-substituted naphthalenoids (1-7, 9, 10, and 13-16) together with four known ones (8, and 11-13) have been designed and synthesized. Their antitumor activities were evaluated by sulforhodamine B assay on human breast cancer MDA-MB-231, human lung cancer A549 and human cervical cancer HeLa cell lines. Four compounds (2, 4, 10 and 12) showed potent inhibitory activities against the growth of the three cell lines with IC50 between 0.34-3.49 μM, and were more potent than the reference etoposide (IC50 3.67-13.78 μM). DNA relaxation assay revealed that compound 2 showed potent inhibitory activity against Topo IIα in vitro. The structure-activity relationships of these compounds were discussed, suggesting that further structural optimizations of aryl-substituted naphthalenoids could lead to the discovery of potent antitumor agents targeting topoisomerases.
    Medicinal chemistry (Shāriqah (United Arab Emirates)) 09/2013; · 1.64 Impact Factor
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    ABSTRACT: A series of novel Ligustrazinyl amides was designed, synthesized and evaluated for their protective effect on the injured vascular endothelial cells. The preliminary results demonstrated that some compounds possessed more potent activities than that of Ligustrazine in stimulating replication of the injured human umbilical vascular endothelial cells (HUVECs) that is damaged by hydrogen peroxide. Among the active compounds, compounds 8i, 8t and 8u exhibited the highest potency with low EC50 values of 0.037, 0.070 and 0.055 mM, respectively. Structure-activity relationships were briefly discussed.
    Medicinal chemistry (Shāriqah (United Arab Emirates)) 09/2013; · 1.64 Impact Factor

Publication Stats

231 Citations
142.64 Total Impact Points

Institutions

  • 2009–2014
    • Shandong University
      • • School of Pharmaceutical Sciences
      • • Institute for Medicine Chemistry
      Chi-nan-shih, Shandong Sheng, China
    • Xuzhou Medical College
      • Department of Hematology
      Suchow, Jiangsu Sheng, China
  • 2013
    • Wuhan General Hospital of Guangzhou Military Command
      Wu-han-shih, Hubei, China
  • 2010–2013
    • Shanxi University
      • School of Chemistry and Chemical Engineering
      Yangkü, Shanxi Sheng, China
  • 2012
    • Peking Union Medical College Hospital
      Peping, Beijing, China
    • Nanjing Medical University
      • Department of Hematology
      Nanjing, Jiangsu Sheng, China