Publications by authors named "Yonghua Liu"

97 Publications

The BCMA-Targeted Fourth-Generation CAR-T Cells Secreting IL-7 and CCL19 for Therapy of Refractory/Recurrent Multiple Myeloma.

Front Immunol 2021 5;12:609421. Epub 2021 Mar 5.

Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.

Chimeric antigen receptor (CAR) technology has revolutionized cancer treatment, particularly in malignant hematological tumors. Currently, the BCMA-targeted second-generation CAR-T cells have showed impressive efficacy in the treatment of refractory/relapsed multiple myeloma (R/R MM), but up to 50% relapse remains to be addressed urgently. Here we constructed the BCMA-targeted fourth-generation CAR-T cells expressing IL-7 and CCL19 (i.e., BCMA-7 × 19 CAR-T cells), and demonstrated that BCMA-7 × 19 CAR-T cells exhibited superior expansion, differentiation, migration and cytotoxicity. Furthermore, we have been carrying out the first-in-human clinical trial for therapy of R/R MM by use of BCMA-7 × 19 CAR-T cells (ClinicalTrials.gov Identifier: NCT03778346), which preliminarily showed promising safety and efficacy in first two enrolled patients. The two patients achieved a CR and VGPR with Grade 1 cytokine release syndrome only 1 month after one dose of CAR-T cell infusion, and the responses lasted more than 12-month. Taken together, BCMA-7 × 19 CAR-T cells were safe and effective against refractory/relapsed multiple myeloma and thus warranted further clinical study.
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http://dx.doi.org/10.3389/fimmu.2021.609421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985831PMC
March 2021

Emergent chikungunya fever and vertical transmission in Yunnan Province, China, 2019.

Arch Virol 2021 May 11;166(5):1455-1462. Epub 2021 Mar 11.

Center for Disease Control and Prevention of Southern Theater Command, Kunming, Yunnan Province, 650118, People's Republic of China.

During the dengue epidemic in Yunnan Province, China, during 2019, a concurrent outbreak of chikungunya occurred in the city of Ruili, which is located in the southwest of the province, adjacent to Myanmar. As part of this outbreak, three neonatal cases of infection with indigenous chikungunya virus from mother-to-child (vertical) transmission were observed. Isolates of chikungunya virus were obtained from 37 serum samples of patients with chikungunya during this outbreak, and a phylogenetic analysis of these isolates revealed that they belong to the Indian Ocean subclade of the East/Central/South African genotype. The E1 genes of these viruses did not harbor the A226V mutation.
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http://dx.doi.org/10.1007/s00705-021-05005-1DOI Listing
May 2021

Trace metal bioaccumulation in oysters (Crassostrea gigas) from Liaodong Bay (Bohai Sea, China).

Environ Sci Pollut Res Int 2021 Apr 6;28(16):20682-20689. Epub 2021 Jan 6.

College of Animal Husbandry and Veterinary, Jinzhou Medical University, No. 40 Songpo Street Linghe District, Jinzhou, 121000, Liaoning Province, China.

Cd, Cr, Cu, Pb, and Zn concentrations were measured in oysters (C. gigas), plankton, and seawater during spring, summer, and autumn in Liaodong Bay (Bohai Sea, China) to elucidate the effects of season, region, and oyster size on metal bioaccumulation in oysters. Metal concentrations were quantified via atomic absorption spectrophotometry. Our study determined that metal concentrations in oysters, plankton, and seawater were the highest in summer, whereas the lowest levels occurred in autumn. Regarding oyster sizes, the highest Pb levels occurred in C3-sized oysters (> 5-cm length), whereas the highest Cd, Cr, Cu, and Zn levels occurred in C2 (3-5-cm length) oysters. In contrast, the lowest Cu and Pb levels occurred in C1 (< 3-cm length) oysters, whereas the lowest mean Cd, Cr, and Zn concentrations were observed in C3 oysters. Significant differences in trace metal concentrations in the three sample types were observed in all sampling sites.
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http://dx.doi.org/10.1007/s11356-020-11968-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099804PMC
April 2021

Multiple MYB Activators and Repressors Collaboratively Regulate the Juvenile Red Fading in Leaves of Sweetpotato.

Front Plant Sci 2020 25;11:941. Epub 2020 Jun 25.

Key Laboratory of Tropical Biological Resources, Ministry of Education, School of Life and Pharmaceutical Sciences, Hainan University, Haikou, China.

Juvenile red fading describes the phenomenon in plants whereby red young leaves gradually turn green as they mature. While this phenomenon is commonly observed, the underlying molecular mechanism is still obscure as the classic model plants do not exhibit this process. Here, the molecular mechanism for the loss of anthocyanins during juvenile red fading were explored in the sweetpotato ( L.) cultivar "Chuanshan Zi". The MYB-bHLH-WDR (MBW) regulatory complexes for anthocyanins were examined with five stages of leaf development from C1 to C5. Alternating accumulation of anthocyanins and chlorophylls caused the leaf color change. Five anthocyanin components were identified by ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS), and their contents were highest at stage C2. Transcriptomic analysis showed massive gene expression alteration during leaf development. The anthocyanin structural genes expressed in sweetpotato leaves were screened and found to be highly comparable with those identified in morning glories. The screened anthocyanin regulatory genes included one bHLH (), one WDR (), three MYB activators (, and ), and five MYB repressors (, , , and ). The expression trends of MYBs were key to the red fading process: the activators were highly expressed in early red leaves and were all accompanied by simultaneously expressed MYB repressors, which may act to prevent excessive accumulation of anthocyanins. The only antagonistic repressor, , was highly expressed in green leaves, and may be critical for declined anthocyanin content at later stages. Further functional verification of the above transcription factors were conducted by promoter activation tests. These tests showed that the MBW complexes of IbMYB1/IbMYB2/IbMYB3-IbbHLH2-IbWDR1 not only activated promoters of anthocyanin structural genes and , but also promoters for and , indicating both hierarchical and feedback regulations. This study outlines the elaborate regulatory network of MBW complexes involving multiple MYBs which allow for the timely accumulation of anthocyanins in sweetpotato leaves. These results may also provide clues for similar studies of juvenile red fading in other plant species.
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http://dx.doi.org/10.3389/fpls.2020.00941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330089PMC
June 2020

Synthesis and structure-activity relationship study of water-soluble carbazole sulfonamide derivatives as new anticancer agents.

Eur J Med Chem 2020 Apr 22;191:112181. Epub 2020 Feb 22.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, PR China. Electronic address:

Here, we formulated and investigated the structure-activity relationships of novel N-substituted carbazole sulfonamide derivatives with improved physicochemical properties. Most of these new compounds displayed good aqueous solubility. Certain molecules presented strong in vitro antiproliferative and in vivo antitumor activity. Relative to the control, 50 mg/kg compound 3v substantially reduced human HepG2 xenograft mouse tumor growth by 54.5% and its efficacy was comparable to that of CA-4P. Compound 3h demonstrated anticancer efficacy in both subcutaneous and orthotopic HepG2 xenograft mouse models. We also developed a novel synthetic method for 7-hydroxy-substituted carbazole sulfonamides. Compared with the control, 25 mg/kg compound 4c inhibited human HepG2 xenograft mouse tumor growth by 71.7% and was more potent than 50 mg/kg CA-4P with only 50% tumor shrinkage efficacy. Among the three water-soluble carbazole sulfonamide derivatives formulated in the present study, compound 4c displayed the most effective tumor growth inhibition in vivo and merit further investigation as potential antitumor agents for cancer therapy.
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http://dx.doi.org/10.1016/j.ejmech.2020.112181DOI Listing
April 2020

Embelin Promotes Oncolytic Vaccinia Virus-Mediated Antitumor Immunity Through Disruption of IL-6/STAT3 Signaling in Lymphoma.

Onco Targets Ther 2020 17;13:1421-1429. Epub 2020 Feb 17.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, People's Republic of China.

Objective: Oncolytic virotherapy is a promising alternative to conventional treatment, yet limited viral replication and immune-negative feedback are the major hurdles to effective viro-immunotherapy.

Methods: In this study, we found that use of an adjuvant of embelin, a small molecular inhibitor of XIAP, increased the replication of oncolytic vaccinia virus (OVV) by mitigating antiviral innate immunity. Moreover, embelin suppresses constitutive STAT3 phosphorylation and mitigates OVV-induced activation of STAT3 in lymphoma. In the subcutaneous lymphoma model, embelin significantly enhanced the therapeutic efficacy of OVV and prolonged the survival. In addition, embelin significantly increased the OVV-induced infiltration of T cells and NK cells and decreased the number of OVV-induced myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment.

Results: Our results explored the ability of OVV and embelin in combination to enhance lymphoma cell lysis, revealing a beneficial combinatorial effect wherein both lymphoma cell lysis and OVV replication were enhanced both in vitro and in an in vivo murine model system.

Conclusion: Our findings indicate the utility of embelin as an adjuvant for oncolytic viro-immunotherapy.
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http://dx.doi.org/10.2147/OTT.S209312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034962PMC
February 2020

Synthesis and in vitro activity of asymmetric indole-based bisamidine compounds against Gram-positive and Gram-negative pathogens.

Bioorg Med Chem Lett 2020 04 13;30(8):126887. Epub 2019 Dec 13.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tian Tan Xi Li 1#, Beijing 100050, China. Electronic address:

A series of new asymmetric bisamidine was designed, synthesized, and tested for their in-vitro antibacterial activity using a range of Gram-positive and Gram-negative pathogens. Most compounds demonstrated powerful antibacterial activity, and interestingly, some displayed better activity against several Gram-negative strains than the lead compound 1. The most potent bisamidine 8l exhibited 4-fold more potent activity against E. coli, K. pneumonia, P. aeruginosa, and C. freundii than compound 1. Especially 8l exhibited a powerful activity against K. pneumonia secreting NDM-1 enzyme with a minimum inhibitory concentration (MIC) of 2 μg/mL, while levofloxacin and vancomycin displayed resistance, with MICs > 128 μg/mL.
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http://dx.doi.org/10.1016/j.bmcl.2019.126887DOI Listing
April 2020

Next-generation sequencing of the mitochondrial genome of (coleoptera: Cerambycidae).

Mitochondrial DNA B Resour 2019 Sep 27;4(2):3266-3267. Epub 2019 Sep 27.

College of Life and Sciences, Yulin University, Yulin, China.

The Juniper Bark Borer belongs to family Colubridae, and is distributed in north China, Japan and the Korean Peninsula. In this study, the total mitochondrial genome of was determined using next-generation sequencing. The whole mitogenome is a typical circular DNA molecule of 16,051 bp and contains 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and one control region, with a base composition of A 40.8%, G 11.0%, T 32.6%, and C 16.6%. Phylogenetic analysis indicated that was the nearest sister to . The molecular data presented here would be useful for further study of .
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http://dx.doi.org/10.1080/23802359.2019.1671245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707332PMC
September 2019

Heat Stress in Legume Seed Setting: Effects, Causes, and Future Prospects.

Front Plant Sci 2019 31;10:938. Epub 2019 Jul 31.

School of Agronomy, Anhui Agricultural University, Hefei, China.

Grain legumes provide a rich resource of plant nutrition to human diets and are vital for food security and sustainable cropping. Heat stress during flowering has a detrimental effect on legume seed yield, mainly due to irreversible loss of seed number. To start with, we provide an overview of the developmental and physiological basis of controlling seed setting in response to heat stress. It is shown that every single process of seed setting including male and female gametophyte development, fertilization, and early seed/fruit development is sensitive to heat stress, in particular male reproductive development in legume crops is especially susceptible. A series of physiochemical processes including heat shock proteins, antioxidants, metabolites, and hormones centered with sugar starvation are proposed to play a key role in regulating legume seed setting in response to heat stress. The exploration of the molecular mechanisms underlying reproductive heat tolerance is in its infancy. , with a small diploid genome, and well-established transformation system and molecular platforms, has become a valuable model for testing gene function that can be applied to advance the physiological and molecular understanding of legume reproductive heat tolerance.
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http://dx.doi.org/10.3389/fpls.2019.00938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684746PMC
July 2019

Cell Wall Invertase and Sugar Transporters Are Differentially Activated in Tomato Styles and Ovaries During Pollination and Fertilization.

Front Plant Sci 2019 18;10:506. Epub 2019 Apr 18.

School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW, Australia.

Flowering plants depend on pollination and fertilization to activate the transition from ovule to seed and ovary to fruit, namely seed and fruit set, which are key for completing the plant life cycle and realizing crop yield potential. These processes are highly energy consuming and rely on the efficient use of sucrose as the major nutrient and energy source. However, it remains elusive as how sucrose imported into and utilizated within the female reproductive organ is regulated in response to pollination and fertilization. Here, we explored this issue in tomato by focusing on genes encoding cell wall invertase (CWIN) and sugar transporters, which are major players in sucrose phloem unloading, and sink development. The transcript level of a major CWIN gene, , and CWIN activity were significantly increased in style at 4 h after pollination (HAP) in comparison with that in the non-pollination control, and this was sustained at 2 days after pollination (DAP). In the ovaries, however, CWIN activity and expression did not increase until 2 DAP when fertilization occurred. Interestingly, a CWIN inhibitor gene was repressed in the pollinated style at 2 DAP. In response to pollination, the style exhibited increased expressions of genes encoding hexose transporters, , , , and sucrose transporters , , and from 4 HAP to 2 DAP. Upon fertilization, and and , but not , were also stimulated in fruitlets at 2 DAP. Together, the findings reveal that styles respond promptly and more broadly to pollination for activation of CWIN and sugar transporters to fuel pollen tube elongation, whereas the ovaries do not exhibit activation for some of these genes until fertilization occurs.

Highlights: Expression of genes encoding cell wall invertases and sugar transporters was stimulated in pollinated style and fertilized ovaries in tomato.
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http://dx.doi.org/10.3389/fpls.2019.00506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482350PMC
April 2019

The functionalized ruthenium(II) polypyridine complexes for the highly selective sensing of mercury ions.

Spectrochim Acta A Mol Biomol Spectrosc 2019 Aug 18;219:141-146. Epub 2019 Apr 18.

Ministry of Education Key Laboratory of Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, College of Chemistry, Fuzhou University, Fuzhou 350116, China. Electronic address:

A series of new ruthenium(II) polypyridine complexes appending with thioether groups were designed, synthesized and characterized. The sensing ability of the complexes toward mercury ions were studied by electronic absorption and emission spectra, and the reaction of the complexes with mercury ions were also confirmed by ESI mass spectroscopy and HNMR spectroscopy. The thioether groups would react with mercury ion fast to form aldehyde group leading to the significant change in the spectra. The color of the complex changed from yellow to orange after addition of mercury ions, and the color of the emission changed from red orange to dark red with a large red shift (~80 nm). Importantly, these kinds of ruthenium(II) complexes show a unique recognition of mercury ions over other metal ions. The complexes with more thioether groups also showed a better sensitivity toward mercury ions, this is good strategy for the further design of the new phosphorescent probes for sensing of mercury ions.
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http://dx.doi.org/10.1016/j.saa.2019.04.043DOI Listing
August 2019

Voltammetric determination of DNA based on regulation of DNA strand displacement using an allosteric DNA toehold.

Mikrochim Acta 2018 08 28;185(9):433. Epub 2018 Aug 28.

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300000, People's Republic of China.

An electrochemical biosensor for determination of DNA is described that is based on the reaction of regulated DNA (reg-DNA) first with substrated DNA (subs-DNA) to form a reaction intermediate. The intermediate binds target DNA (T) by hybridization and initiates a branch migration leading to the production of complex of substrated DNA and target DNA (TC). Once TC is produced, it reacts with assisted DNA (ass-DNA) through a toehold exchange mechanism, yielding the product complex of substrated DNA and assisted DNA (CS). The target is then released back into the solution and and catalyzes the next cycle of toehold-exchange with the reaction intermediate of substrated DNA and regulated DNA (CPR). Unlike in a conventional DNA toehold that is hardwired with the branch migration domain, the allosteric DNA toehold is designed into a reg-DNA which is independent of the branch migration domain. Under the optimal experimental conditions and at a working potential as low as 0.18 V, response to DNA is linear in the 1 fM to 1000 pM concentration range, and the detection limit is 0.83 fM. The assay is highly specific and can discriminate target DNA even from a single-base mismatch. It was applied to the analysis of DNA spiked plasma samples. Graphical abstract Schematic illustration of the electrochemical strategy for target DNA detection based on regulation of DNA strand displacement using an allosteric DNA toehold strategy. It can be used to analyze DNA-spiked plasma samples and has a low detection limit of 0.83 fM.
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http://dx.doi.org/10.1007/s00604-018-2967-3DOI Listing
August 2018

CYP2C9 and OATP1B1 genetic polymorphisms affect the metabolism and transport of glimepiride and gliclazide.

Sci Rep 2018 Jul 20;8(1):10994. Epub 2018 Jul 20.

Clinical Pharmacology Institute, Nanchang University, Nanchang, 330006, Republic of China.

The therapeutic use of glimepiride and gliclazide shows substantial inter-individual variation in pharmacokinetics and pharmacodynamics in human populations, which might be caused by genetic differences among individuals. The aim of this study was to assess the effect of CYP2C9 and OATP1B1 genetic polymorphisms on the metabolism and transport of glimepiride and gliclazide. The uptake of glimepiride and gliclazide was measured in OATP1B1*1a, *5 and *15-HEK293T cells, and their metabolism was measured using CYP2C9*1, *2 and *3 recombinase by LC-MS. Glimepiride in OATP1B1*1a, *5 and *15-HEK293T cells had V values of 155 ± 18.7, 80 ± 9.6, and 84.5 ± 8.2 pmol/min/mg, while gliclazide had V values of 15.7 ± 4.6, 7.2 ± 2.5, and 8.7 ± 2.4 pmol/min/mg, respectively. The clearance of glimepiride and gliclazide in OATP1B1*5 and *15 was significantly reduced compared to the wild-type. Glimepiride in the presence of CYP2C9*1, *2 and *3 recombinase had V values of 21.58 ± 7.78, 15.69 ± 5.59, and 9.17 ± 3.03 nmol/min/mg protein, while gliclazide had V values of 15.73 ± 3.11, 10.53 ± 4.06, and 6.21 ± 2.94 nmol/min/mg protein, respectively. The clearance of glimepiride and gliclazide in CYP2C9*2 and *3 was significantly reduced compared to the wild-type. These findings collectively indicate that OATP1B1*5 and *15 and CYP2C9*2 and *3 have a significant effect on the transport and metabolism of glimepiride and gliclazide.
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http://dx.doi.org/10.1038/s41598-018-29351-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054689PMC
July 2018

Vasodilator-stimulated phosphoprotein-guided Clopidogrel maintenance therapy reduces cardiovascular events in atrial fibrillation patients requiring anticoagulation therapy and scheduled for percutaneous coronary intervention: a prospective cohort study.

BMC Cardiovasc Disord 2018 06 18;18(1):120. Epub 2018 Jun 18.

Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China.

Background: In a previous study, we found that titrating clopidogrel maintenance doses (MDs) according to vasodilator-stimulated phosphoprotein (VASP) monitoring minimised the rate of major adverse cardiovascular and cerebral events (MACCE) after percutaneous coronary intervention (PCI) without increasing bleeding in patients with high on-treatment platelet reaction to clopidogrel. This study aimed to investigate whether VASP-guided clopidogrel MD could reduce thromboembolism and bleeding in atrial fibrillation (AF) patients requiring anticoagulation and scheduled for PCI.

Methods: AF patients scheduled for PCI were recruited between July 2014 and July 2016. These patients were allocated into VASP-guided (n = 250) and control (n = 253) groups depending on the clopidogrel MD profile. In the VASP-guided group, clopidogrel MD was titrated by the platelet reactivity index (PRI), whereas in the control group, clopidogrel MD was fixed at 75 mg per day. The primary endpoint was MACCE and secondary endpoints were thrombolysis in myocardial infarction (TIMI) major and minor bleeding 1 year after PCI.

Results: Five hundred and three patients were included in the present study, with 1-year data available for 95.6% patients. The average CHADS-VASc score of the whole population was 3.7 ± 0.7 and the average HAS-BLED score was 3.2 ± 0.4. MACCE was less in the VASP-guided group than in the control group (2.5% vs. 5.0%, P = 0.02). The incidence of major bleeding was comparable between both groups (3.0% vs. 2.8%, P = 0.72) and minor bleeding was higher in the VASP-guided group than in the control group (15.3% vs. 9.7%, P = 0.03). Kaplan-Meier analysis indicated that there was no difference in survival between both groups (log-rank test, P = 0.68).

Conclusions: In AF patients requiring anticoagulation and scheduled for PCI, VASP-guided antiplatelet therapy reduced major cardiovascular and cerebral adverse events, accompanied by increased minor bleeding events.

Trial Registration: The present study was retrospectively registered in the Chinese Clinical Trial Registry, A Primary Registry of the International Clinical Trial Registry Platform, World Health Organisation (Registration no: ChiCTR-IOR-17013854 ). The registered date was December 11, 2117.
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http://dx.doi.org/10.1186/s12872-018-0853-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006722PMC
June 2018

Coupling coumarin to gold nanoparticles by DNA chains for sensitive detection of DNase I.

Anal Biochem 2018 08 6;555:50-54. Epub 2018 Jun 6.

Key Laboratory of Analysis and Detection Technology for Food Safety (Ministry of Education and Fujian Province), Department of Chemistry, Fuzhou University, Fuzhou, 350116, China. Electronic address:

A kind of coumarin-modified gold nanoparticle by the bridge of dsDNA chains was designed and synthesized for sensitive detection of DNase I. The fluorescence of coumarin 343 at emission wavelengths of 491 nm excited at 440 nm was quenched by the gold nanoparticles due to the energy transfer process after the coumarin 343 was connected on the gold nanoparticles by DNA chains. When dsDNA chains were cut off by DNase I, the coumarin 343 molecules were released from gold nanoparticles and the fluorescence of coumarin 343 would be restored. The DNase I activity could be detected by this fluorescence assay with a high sensitivity based on the change of the energy transfer efficiency. The intensity of restored fluorescence is linearly related to the quantity of DNase I in the range from 1.0 to 40 mU/mL with a detection limit of 0.22 mU/mL. This design idea could render a useful way to develop similar molecular or enzyme sensor in analytical or biological fields.
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http://dx.doi.org/10.1016/j.ab.2018.06.002DOI Listing
August 2018

Synthesis and structure-activity relationship of novel bisindole amidines active against MDR Gram-positive and Gram-negative bacteria.

Eur J Med Chem 2018 Apr 12;150:771-782. Epub 2018 Mar 12.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tian Tan Xi Li 1#, Beijing, 100050, China. Electronic address:

A series of novel diamidines with N-substituents on an amidine N-atom were synthesized and evaluated for their cytotoxicity and in vitro antibacterial activity against a range of Gram-positive and Gram-negative bacterial strains. Based on structure-activity relationship, N-substituents with a branched chain and a shorter carbon chain on the amidine N-atom exhibited more promising activity against Gram-negative and MDR-Gram-positive bacteria; compounds 5c and 5i were the most powerful candidate compounds. Compound 5c showed greater efficacy than levofloxacin against most drug-resistant Gram-positive bacteria and exhibited broad-spectrum antibacterial activity against Gram-negative bacteria, with MIC values in the range of 2-16 μg/mL. Slightly more potent antibacterial activity against Klebsiella pneumoniae, Acinetobacter calcoaceticus, Enterobacter cloacae, and Proteus mirabilis was observed for 5i in comparison with 5c. Compound 5i also showed remarkable antibacterial activity against NDM-1-producing Gram-negative bacteria, with MIC values in the range of 2-4 μg/mL, and was superior to the reference drugs meropenem and levofloxacin. Effective antibacterial activity of 5i was also shown in vivo in a mouse model of Staphylococcus aureus MRSA strain, with an EDvalues of 2.62 mg/kg.
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http://dx.doi.org/10.1016/j.ejmech.2018.03.031DOI Listing
April 2018

Serum calcitonin negative mixed medullary-follicular carcinoma initially diagnosed as medullary thyroid carcinoma by fine-needle aspiration cytology: A case report and review of the literatures.

Diagn Cytopathol 2018 Aug 10;46(8):690-693. Epub 2018 Mar 10.

Department of Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Medullary thyroid carcinoma (MTC) is potentially lethal. A prompt and accurate diagnosis is the prerequisite for the treatment of MTC. Fine-needle aspiration (FNA) is a reliable diagnostic tool in the assessment of thyroid nodules. However, cytologic assessment of MTC based on FNA has several drawbacks due to morphological variants. We present a case of MTC diagnosed through FNA cytology, which was eventually histologically confirmed as a mixed medullary-follicular carcinoma with negative serum calcitonin expression. Hence, diagnosis of MTC based on FNA should be applied with caution. Ultrasound characteristics of suspicious thyroid nodules are recommended to be evaluated by FNA. However, calcitonin levels should be measured in both the FNA washout fluid and serum when features of MTC are presented or cytology result is inconclusive. If adequate FNA sample is available, a supplementary immunocytochemical staining of markers such as calcitonin, chromogranin, carcinoembryonic antigen, and thyroglobulin is helpful for a correct diagnosis of MTC.
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http://dx.doi.org/10.1002/dc.23924DOI Listing
August 2018

Novel carbazole sulfonamide microtubule-destabilizing agents exert potent antitumor activity against esophageal squamous cell carcinoma.

Cancer Lett 2018 04 31;420:60-71. Epub 2018 Jan 31.

State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China. Electronic address:

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide due to its chemoresistance and poor prognosis. Currently, there is a lack of effective small molecule drugs for the treatment of ESCC. Microtubules are an attractive target for cancer therapy since they play a central role in various fundamental cell functions. We investigated the anti-ESCC activity and mechanisms of the small molecule tubulin ligands, SL-3-19 and SL-1-73, which are two carbazole sulfonamide derivatives, in vitro and in vivo for the first time. These drugs were previously screened from a small molecule library with over 450 compounds and optimized for high aqueous solubility [1,2]. Here, we reveal the promising activities of these compounds against esophageal cancer. Mechanistically, both SL-3-19 and SL-1-73 inhibited ESCC cell growth by inducing cell apoptosis and arresting the cell cycle at G2/M phase in a dose-dependent manner. These drugs effectively inhibited microtubule assembly, greatly disrupted microtubule maturation by down-regulating acetylated α-tubulin, and significantly disrupted the vascular structure by obstructing the formation of capillary-like tubes in vitro. Consistent with their in vitro activities, SL-3-19 and SL-1-73 inhibited the growth of ESCC xenografts and inhibited the microvessel density in vivo. In summary, SL-3-19 and SL-1-73 are novel microtubule-destabilizing agents that have a potential antitumor effect on ESCC both in vitro and in vivo, and SL-3-19 had a higher activity than SL-1-73, with a low IC value and an observable antitumor activity in vivo. These results indicate that SL-3-19 may be a new therapeutic candidate for ESCC treatment.
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http://dx.doi.org/10.1016/j.canlet.2018.01.066DOI Listing
April 2018

Long non-coding RNA FTH1P3 facilitates uveal melanoma cell growth and invasion through miR-224-5p.

PLoS One 2017 2;12(11):e0184746. Epub 2017 Nov 2.

Department of Ophthalmology, Liaocheng People's Hospital, Liaocheng, Shandong, China.

Growing evidences indicated that Long noncoding RNAs (lncRNAs) played important roles in tumor initiation and progression. However, the function and mechnism of lncRNA ferritin heavy chain 1 pseudogene 3 (FTH1P3) remain unknown in uveal melanoma. We showed that the expression level of FTH1P3 was upregulated in uveal melanoma cell lines and tissues. Elevated expression of FTH1P3 promoted uveal melanoma cell proliferation, cell cycle and migration. Moreover, we found that FTH1P3 was a direct target gene of miR-224-5p in uveal melanoma cell. Overexpression of FTH1P3 suppressed miR-224-5p expression and promoted the expression of Rac1 and Fizzled 5, which were the direct target genes of miR-224-5p. Furthermore, we showed that miR-224-5p expression level was downregulated in uveal melanoma cell lines and tissues. FTH1P3 expression was inversely correlated with the miR-224-5p expression in uveal melanoma tissues. Ectopic expression of miR-224-5p decreased uveal melanoma cell proliferation, cell cycle and migration. Elevated expression of FTH1P3 enhanced uveal melanoma cell proliferation and migration by inhibiting miR-224-5p expression. These results suggest that lncRNA FTH1P3 plays a crucial role in uveal melanoma. Investigation of the underlying mechanism may be a target for the treatment of uveal melanoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184746PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667836PMC
December 2017

Efficacy and advantages of modified Traditional Chinese Medicine treatments based on "kidney reinforcing" for chronic aplastic anemia: a randomized controlled clinical trial.

J Tradit Chin Med 2016 08;36(4):434-43

Objective: To compare the efficacy of modified treatments based on "kidney reinforcing" in the management of chronic aplastic anemia (CAA), and explore their advantages and specialties.

Methods: One hundred and eleven patients with CAA were randomly divided into three groups: kidney reinforcing alone (KA), "kidney reinforcing and Qi tonifying" (KQ), and "kidney reinforcing and blood circulation invigorating" (KC). Normal and positive control groups were also formed. All patients were treated for 6 months (two courses). Hemograms, Traditional Chinese Medicine (TCM) syndrome scores, and therapeutic effects were assessed, and changes in T-lymphocyte subsets, regulatory T cells and cytokines were detected.

Results: The KQ and KC groups had lower TCM syndrome scores than the positive control group after 6 months (P < 0.05). The KQ group had a higher overall efficacy than the positive control group after 3 months (P < 0.05), while platelet counts increased in the KC group after 6 months (P < 0.05). CD3+ T-lymphocyte ratios decreased only in the KQ group, while CD3 + CD4 + CD8 − Tlymphocytes increased only in the KC group after 6 months (P < 0.05). Levels of interferon-γ, tumor necrosis factor tor-α, interleukin (IL)-2 and IL-6 decreased and levels of IL-4 and IL-10 increased in all treated groups after 6 months. Levels of IL-6 in the KQ and KC groups were lower than those in the positive control group (P < 0.05).

Conclusion: Treatments based on kidney reinforcing have a rebalancing effect on cytotoxic and T helper cells, and regulate expression of interferon- γ, IL-2, IL-6 and IL-4. KQ may be more effective in treating CAA, and KC may have an advantage in platelet recovery.
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http://dx.doi.org/10.1016/s0254-6272(16)30059-0DOI Listing
August 2016

A case report of hereditary spherocytosis with concomitant chronic myelocytic leukemia.

Open Med (Wars) 2016 17;11(1):152-154. Epub 2016 May 17.

Department of Hematology, the People's Hospital of Liushui, Lishui 323000, Zhejiang Province, China.

Hereditary spherocytosis (HS) and Chronic myelocytic leukemia (CML) are both life threatening hemotologic diseases. They are rarely seen to occur simultaneously in one individual patient. Here we demonstrate a case of HS associated with CML in this study. The patient is a young female, diagnosed with HS in 2005, and was given partial embolization of the splenic artery. She got significant remission after the procedure. In 2008, she was found abnormal in blood routine test, after bone marrow routine, chromosome and fusion gene tests, she was diagnosed with CML (chronic phase). She did not receive regular treatment until 3 months prior, and is currently being treated with Dasatimib. She achieved hematological remission, but had no significant improvement in chromosome and fusion gene figures. Due to her severe condition of hemolysis, a splenectomy or an allogeneic hematopoietic stem cell transplantation is considered.
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http://dx.doi.org/10.1515/med-2016-0029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329816PMC
May 2016

Synthesis and in vitro activity of dicationic indolyl diphenyl ethers as novel potent antibiotic agents against drug-resistant bacteria.

Bioorg Med Chem Lett 2017 02 10;27(4):841-844. Epub 2017 Jan 10.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tian Tan Xi Li 1#, Beijing 100050, China. Electronic address:

A series of 4,4'-bis-[2-(6-N-substituted-amidino)indolyl] diphenyl ether have been synthesized and tested for their in vitro antibacterial activity including a range of Gram-positive and Gram-negative pathogens and cytotoxicity. Most of these compounds have mainly shown anti-Gram positive bacteria activities especially against drug resistant bacterial strains MRSA, MRSE and VRE. The anti-MRSA and anti-MRSE activities of compound 7a and 7j were more potent than that of the lead compound 2, levofloxacin and vancomycin. Interestingly, 7j had greatly improved anti negative bacterial activity, especially for the producing NDM-1 Klebsiella pneumonia strain and less toxic than that of the lead compound 2.
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http://dx.doi.org/10.1016/j.bmcl.2017.01.019DOI Listing
February 2017

The Expression of NP847 and Sox2 after TBI and Its Influence on NSCs.

Front Cell Neurosci 2016 22;10:282. Epub 2016 Dec 22.

Department of Neurosurgery, Affiliated Hospital of Nantong University Nantong, China.

The proliferation and differentiation of neural stem cells (NSCs) is important for neural regeneration after cerebral injury. Here, for the first time, we show that phosphorylated (p)-ser847-nNOS (NP847), rather than nNOS, may play a major role in NSC proliferation after traumatic brain injury (TBI). Western blot results demonstrated that the expression of NP847 and Sox2 in the hippocampus is up-regulated after TBI, and they both peak 3 days after brain injury. In addition, an immunofluorescence experiment indicated that NP847 and Sox2 partly co-localize in the nuclei of NSCs after TBI. Further immunoprecipitation experiments found that NP847 and Sox2 can directly interact with each other in NSCs. Moreover, in an OGD model of NSCs, NP847 expression is decreased, which is followed by the down-regulation of Sox2. Interestingly, in this study, we did not observe changes in the expression of nNOS in the OGD model. Further research data suggest that the NP847-Sox2 complex may play a major role in NSCs through the Shh/Gli signaling pathway in a CaMKII-dependent manner after brain injury.
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http://dx.doi.org/10.3389/fncel.2016.00282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177638PMC
December 2016

Upregulated Expression of TRIM32 Is Involved in Schwann Cell Differentiation, Migration and Neurite Outgrowth After Sciatic Nerve Crush.

Neurochem Res 2017 Apr 26;42(4):1084-1095. Epub 2016 Dec 26.

Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.

Tripartite motif containing 32 (TRIM32), a member of the tripartite motif (TRIM) family, plays an indispensable role in myoblast proliferation. It also regulates neuron and skeletal muscle stem cell differentiation. Although it is of great importance, we know little about the roles of TRIM32 during peripheral nervous system injury. Here, we examined the dynamic changes of TRIM32 in acute sciatic nerve crush (SNC) model. After crush, TRIM32 rapidly increased and reached the climax at 1 week but then gradually declined to the normal level at 4 weeks post-injury. Meanwhile, we observed similar changes of Oct-6. What is more, we found co-localization of TRIM32 with S100 and Oct-6 in 1-week-injured tissues using double immunofluorescent staining. In further vitro experiments, enhancive expression of TRIM32 was detected during the process of cyclic adenosine monophosphate (cAMP)-induced Schwann cell differentiation and nerve growth factor (NGF)-induced PC12 cell neurite outgrowth. More interestingly, specific si-TRIM32-transfected RSC96 cells exhibited obvious reduction in the ability of migration. Taken together, we inferred that upregulated TRIM32 was not only involved in the differentiation and migration of Schwann cells but the neurite elongation after SNC.
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http://dx.doi.org/10.1007/s11064-016-2142-3DOI Listing
April 2017

Novel carbazole sulfonamide derivatives of antitumor agent: Synthesis, antiproliferative activity and aqueous solubility.

Bioorg Med Chem Lett 2017 01 25;27(2):261-265. Epub 2016 Nov 25.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, People's Republic of China. Electronic address:

The current optimization of IG-105 (3) on the carbazole-ring provided a series of new carbazole sulfonamides derivatives 13a-13m. All of the compounds have been evaluated against HepG2 cells (hepatoma cancer) for antiproliferative activity. Compounds that showed activity better or comparable to that of 3 versus HepG2 were evaluated against MCF-7 (breast cancer), MIA PaCa-2 (pancreatic cancer), and Bel-7402 (hepatoma/liver cancer) for antiproliferative activity. Of the seven compounds selected for further study five (13b, 13g, 13j, 13k and 13l) were found to give IC values against the four cell lines comparable to those for 3. Two compounds (13f and 13i) were more active than 3 and their activity against HepG2 and MCF-7 (IC:0.01-0.07μM) approached that of the positive controls podophyllotoxin (podo) and CA-4. Most of compounds showed aqueous solubility (0.11-19.60μg/mL at pH 7.4 and 2.0) better than 3. These promising results warrant further development of new compounds 13f and 13i as potential potent antitumor drug candidates.
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http://dx.doi.org/10.1016/j.bmcl.2016.11.068DOI Listing
January 2017

The Expression of IGFBP6 after Spinal Cord Injury: Implications for Neuronal Apoptosis.

Neurochem Res 2017 Feb 26;42(2):455-467. Epub 2016 Nov 26.

Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China.

IGFBP6, a member of the insulin-like growth factor-binding proteins family that contains six high affinity IGFBPs, modulates insulin-like growth factor (IGF) activity and also showed an independent effect of IGF, such as growth inhibition and apoptosis. However, the role of IGFBP6 in spinal cord injury (SCI) remains largely elusive. In this study, we have performed an acute SCI model in adult rats and investigated the dynamic changes of IGFBP6 expression in the spinal cord. Our results showed that IGFBP6 was upregulated significantly after SCI, which was paralleled with the levels of apoptotic proteins p53 and active caspase-3. Immunofluorescent labeling showed that IGFBP6 was co-localizated with active caspase-3 and p53 in neurons. To further investigate the function of IGFBP6, an apoptosis model was established in primary neuronal cells. When IGFBP6 was knocked down by specific short interfering RNA (siRNA), the protein levels of active caspase-3 and Bax as well as the number of apoptotic primary neurons were significantly decreased in our study. Taken together, our findings suggest that the change of IGFBP6 protein expression plays a key role in neuronal apoptosis after SCI.
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http://dx.doi.org/10.1007/s11064-016-2092-9DOI Listing
February 2017

Upregulation of PLZF is Associated with Neuronal Injury in Lipopolysaccharide-Induced Neuroinflammation.

Neurochem Res 2016 Nov 19;41(11):3063-3073. Epub 2016 Aug 19.

Department of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China.

Promyelocytic leukemia zinc finger (PLZF) protein has been identified as a tumor suppressor in a variety of cancers, including leukemia, malignant mesothelioma, malignant melanoma, pancreatic cancer and prostate cancer. Studies have demonstrated that altered expression of PLZF affected its biological functions associated with tumorigenesis, such as proliferation, cell cycle, and apoptosis. However, information regarding its regulation and possible function in the central nervous system diseases is still limited. In this study, we performed a neuroinflammatory model by lipopolysaccharide (LPS) lateral ventricle injection in adult rats and detected increased expression of PLZF in the brain cortex. Immunofluorescence assay indicated that PLZF was significantly increased in neurons 3 day after LPS injection, but not in astrocytes and microglia. Moreover, there was a concomitant upregulation of active caspase-3, cyclin D1, and CDK4 in vivo and vitro studies. In addition, the expression of these proteins in cortical primary neurons was inhibited after knocking down PLZF by siRNA. Collectively, all these results suggested that the upregulation of PLZF might be involved in neuronal apoptotic-like injury in neuroinflammation after LPS injection.
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http://dx.doi.org/10.1007/s11064-016-2027-5DOI Listing
November 2016

Upregulation of PSMB4 is Associated with the Necroptosis after Spinal Cord Injury.

Neurochem Res 2016 Nov 11;41(11):3103-3112. Epub 2016 Aug 11.

Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong University, Haier Lane North Road No. 6, Nantong, 226001, Jiangsu, China.

Spinal cord injury (SCI) is one of the most common and severe complications in spine injury. It is difficult to prevent cell necroptosis and promote the survival of residual neurons after SCI. Proteasome beta-4 subunit (PSMB4) is the first proteasomal subunit with oncogenic properties promoting cancer cell survival and tumor growth in vivo, and our previous study showed that PSMB4 is significantly associated with neuronal apoptosis in neuroinflammation. However, PSMB4 function in the necroptosis after SCI is unkown. RIP3, a key regulatory factor of necroptosis, correlates with the induction of necroptosis in various types of cells and signaling pathway. Upregulation of the RIP3 expression may play a role as a novel molecular mechanism in secondary neural tissue damage following SCI. In this study, we established an acute spinal cord contusion injury model in adult rats to investigate the potential role of PSMB4 during the pathological process of SCI. We found PSMB4 expression was significantly up-regulated 3 days after injury by western blot and immunohistochemical staining. Double immunofluorescent staining indicated obvious changes of PSMB4 expression occurred in neurons. Significant up-regulation of PSMB4 expression was observed in Rip3 positive neurons at 3 days after SCI, which indicated that PSMB4 might play a vital role in the regulation of Rip3. Overexpress and knockdown PSMB4 could intervene the RIP3 and Mixed lineage kinase domain-like protein (MLKL) pathway in Tumor necrosis factor-α (TNF-α) induced necroptosis cell model. Based on our experimental data, we boldly conclude that PSMB4 is associated with RIP3 involved necroptosis after SCI.
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http://dx.doi.org/10.1007/s11064-016-2033-7DOI Listing
November 2016

SCY1-Like 1-Binding Protein 1 (SCYL1BP1) Suppressed Sciatic Nerve Regeneration by Enhancing the RhoA Pathway.

Mol Neurobiol 2016 11 16;53(9):6342-6354. Epub 2015 Nov 16.

Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, Jiangsu, 226001, People's Republic of China.

SCY1-like 1-binding protein 1 (SCYL1BP1) is first identified as an interacting protein with SCYL1. Since SCYL1BP1 is a soluble protein with coiled-coil domains known to be relevant with transcriptional regulation, it has been found to activate the transcription of murine double minute 2 (MDM2) and participate in neurite outgrowth and regeneration. However, the role and mechanism of SCYL1BP1 in peripheral nerve system lesion and repair are still unknown. Here in vitro, our work demonstrated that SCYL1BP1 inhibited cAMP-induced primary Schwann cell differentiation and suppressed nerve growth factor-mediated neurite outgrowth in PC12 cells by enhancing the RhoA pathway. Furthermore, we found that pretreatment with a Rho kinase inhibitor Y-27632 resulted in partial rescue of Schwann cell differentiation and neurite outgrowth. In vivo experiments showed that SCYL1BP1 could also suppress nerve fiber regeneration. In conclusion, we speculated that SCYL1BP1 participated in Schwann cell (SC) differentiation and neurite outgrowth in the sciatic nerve after crush by regulating the RhoA pathway.
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http://dx.doi.org/10.1007/s12035-015-9531-5DOI Listing
November 2016