Publications by authors named "Zhongling Wen"

8 Publications

  • Page 1 of 1

Design, synthesis and biological evaluation of anilide (dicarboxylic acid) shikonin esters as antitumor agents through targeting PI3K/Akt/mTOR signaling pathway.

Bioorg Chem 2021 Mar 29;111:104872. Epub 2021 Mar 29.

State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address:

Triple-negative breast cancer (TNBC) has an unfavorable prognosis attribute to its low differentiation, rapid proliferation and high distant metastasis rate. PI3K/Akt/mTOR as an intracellular signaling pathway plays a key role in the cell proliferation, migration, invasion, metabolism and regeneration. In this work, we designed and synthesized a series of anilide (dicarboxylic acid) shikonin esters targeting PI3K/Akt/mTOR signaling pathway, and assessed their antitumor effects. Through three rounds of screening by computer-aided drug design method (CADD), we preliminarily obtained sixteen novel anilide (dicarboxylic acid) shikonin esters and identified them as excellent compounds. CCK-8 assay results demonstrated that compound M9 exhibited better antiproliferative activities against MDA-MB-231, A549 and HeLa cell lines than shikonin (SK), especially for MDA-MB-231 (M9: IC = 4.52 ± 0.28 μM; SK: IC = 7.62 ± 0.26 μM). Moreover, the antiproliferative activity of M9 was better than that of paclitaxel. Further pharmacological studies showed that M9 could induce apoptosis of MDA-MB-231 cells and arrest the cell cycle in G2/M phase. M9 also inhibited the migration of MDA-MB-231 cells by inhibiting Wnt/β-catenin signaling pathway. In addition, western blot results showed that M9 could inhibit cell proliferation and migration by down-regulating PI3K/Akt/mTOR signaling pathway. Finally, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was also constructed to provide a basis for further development of shikonin derivatives as potential antitumor drugs through structure-activity relationship analysis. To sum up, M9 could be a potential candidate for TNBC therapy.
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http://dx.doi.org/10.1016/j.bioorg.2021.104872DOI Listing
March 2021

Differential relieving effects of shikonin and its derivatives on inflammation and mucosal barrier damage caused by ulcerative colitis.

PeerJ 2021 7;9:e10675. Epub 2021 Jan 7.

State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.

Background: Ulcerative colitis (UC) is one of the most challenging human diseases. Natural shikonin (SK) and its derivatives (with have higher accumulation) isolated from the root of have numerous beneficial effects, such as wound healing and anti-inflammatory activities. Some researchers have reported that hydroxynaphthoquinone mixture (HM) and SK attenuate the acute UC induced by dextran sulfate sodium (DSS). However, no existing study has systemically investigated the effectiveness of SK and other hydroxynaphthoquinone natural derivative monomers on UC.

Methods: In this study, mice were treated with SK and its derivatives (25 mg/kg) and mesalazine (200 mg/kg) after DSS administration daily for one week. Disease progression was monitored daily by observing the changes in clinical signs and body weight.

Results: Intragastric administration natural single naphthoquinone attenuated the malignant symptoms induced by DSS. SK or its derivatives remarkably suppressed the serum levels of pro-inflammatory cytokines while increasing the inflammatory cytokine interleukin (IL)-10 . Additionally, both SK and alkanin restrained the activities of cyclooxygenase-2 (COX-2), myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) in serum and colonic tissues. SK and its derivatives inhibited the activation of nucleotide binding oligomerization domain-like receptors (NLRP3) inflammasome and NF-κB signaling pathway, thereby relieving the DSS-induced disruption of epithelial tight junction (TJ) in colonic tissues.

Conclusions: Our findings shed more lights on the pharmacological efficacy of SK and its derivatives in UC against inflammation and mucosal barrier damage.
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http://dx.doi.org/10.7717/peerj.10675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797173PMC
January 2021

Impact of a G2-EPSPS & GAT Dual Transgenic Glyphosate-Resistant Soybean Line on the Soil Microbial Community under Field Conditions Affected by Glyphosate Application.

Microbes Environ 2020 ;35(4)

Institute for Plant Molecular Biology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University.

In the past thirty years, the biosafety of the aboveground part of crops, including horizontal gene transferal through pollen dispersal and hybridization, has been the focus of research; however, microbial communities in the underground part are attracting increasing attention. In the present study, the soybean root-associated bacterial communities of the G2-EPSPS plus GAT transgenic soybean line Z106, its recipient variety ZH10, and Z106 treated with glyphosate (Z106J) were compared at the seedling, flowering, and seed filling stages by high-throughput sequencing of the V4 hypervariable regions of 16S rRNA gene amplicons using Illumina MiSeq. The results obtained showed no significant differences in the alpha/beta diversities of root-associated bacterial communities at the three stages among ZH10, Z106, and Z106J under field growth conditions; however, the relative abundance of four main nitrogen-fixing bacterial genera significantly differed among ZH10, Z106, and Z106J. Ternary plot results indicated that in the root compartment, the proportional contributions of rhizobial nitrogen-fixing Ensifer fredii and Bradyrhizobium elkanii, which exhibit an extremely broad nodulation host range, markedly differed among the three treatments at the three stages. Thus, the present results indicate that transgenic G2-EPSPS and GAT soybean may induce different changes in functional bacterial species in soil, such as E. fredii and B. elkanii, from ZH10, which were compensated for/enriched at the flowering and seed filling stages, respectively, to some extent through as of yet unknown mechanisms by transgenic soybean treated with glyphosate.
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http://dx.doi.org/10.1264/jsme2.ME20056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734404PMC
January 2020

Dissemination and loss of a biofilm-related genomic island in marine Pseudoalteromonas mediated by integrative and conjugative elements.

Environ Microbiol 2017 11 8;19(11):4620-4637. Epub 2017 Nov 8.

Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, the South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.

Acquisition of genomic islands (GIs) plays a central role in the diversification and adaptation of bacteria. Some GIs can be mobilized in trans by integrative and conjugative elements (ICEs) or conjugative plasmids if the GIs carry specific transfer-related sequences. However, the transfer mechanism of GIs lacking such elements remains largely unexplored. Here, we investigated the transmissibility of a GI found in a coral-associated marine bacterium. This GI does not carry genes with transfer functions, but it carries four genes required for robust biofilm formation. Notably, this GI is inserted in the integration site for SXT/R391 ICEs. We demonstrated that acquisition of an SXT/R391 ICE results in either a tandem GI/ICE arrangement or the complete displacement of the GI. The GI displacement by the ICE greatly reduces biofilm formation. In contrast, the tandem integration of the ICE with the GI in cis allows the GI to hijack the transfer machinery of the ICE to excise, transfer and re-integrate into a new host. Collectively, our findings reveal that the integration of an ICE into a GI integration site enables rapid genome dynamics and a new mechanism by which SXT/R391 ICEs can augment genome plasticity.
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http://dx.doi.org/10.1111/1462-2920.13925DOI Listing
November 2017

MqsR/MqsA Toxin/Antitoxin System Regulates Persistence and Biofilm Formation in KT2440.

Front Microbiol 2017 9;8:840. Epub 2017 May 9.

Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of SciencesGuangzhou, China.

Bacterial toxin/antitoxin (TA) systems have received increasing attention due to their prevalence, diverse structures, and important physiological functions. In this study, we identified and characterized a type II TA system in a soil bacterium KT2440. This TA system belongs to the MqsR/MqsA family. We found that PP_4205 (MqsR) greatly inhibits cell growth in KT2440 and , the antitoxin PP_4204 (MqsA) neutralizes the toxicity of the toxin MqsR, and the two genes encoding them are co-transcribed. MqsR and MqsA interact with each other directly and MqsA is a negative regulator of the TA operon through binding to the promoter. Consistent with the MqsR/MqsA pair in , the binding of the toxin MqsR to MqsA inhibits the DNA binding ability of MqsA in KT2440. Disruption of the gene which induces expression increases persister cell formation 53-fold, while overexpressing which represses expression reduces persister cell formation 220-fold, suggesting an important role of MqsR in persistence in KT2440. Furthermore, both MqsR and MqsA promote biofilm formation. As a DNA binding protein, MqsA can also negatively regulate an ECF sigma factor AlgU and a universal stress protein PP_3288. Thus, we revealed an important regulatory role of MqsR/MqsA in persistence and biofilm formation in KT2440.
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http://dx.doi.org/10.3389/fmicb.2017.00840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422877PMC
May 2017

Interaction of Type IV Toxin/Antitoxin Systems in Cryptic Prophages of Escherichia coli K-12.

Toxins (Basel) 2017 03 1;9(3). Epub 2017 Mar 1.

Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, Research Network for Applied Microbiology (RNAM) Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.

Toxin/antitoxin (TA) systems are widespread in prokaryotic chromosomes and in mobile genetic elements including plasmids and prophages. The first characterized Type IV TA system CbtA/CbeA was found in cryptic prophage CP4-44 in K-12. Two homologous TA loci of CbtA/CbeA also reside in cryptic prophages of K-12, YkfI/YafW in CP4-6 and YpjF/YfjZ in CP4-57. In this study, we demonstrated that YkfI and YpjF inhibited cell growth and led to the formation of "lemon-shaped" cells. Prolonged overproduction of YkfI led to the formation of "gourd-shaped" cells and immediate cell lysis. YafW and YfjZ can neutralize the toxicity of YkfI or YpjF. Furthermore, we found that YkfI and YpjF interacted with cell division protein FtsZ in , but ectopic expression in and did not cause the formation of "lemon-shaped" cells. Moreover, deletion of all of the three toxin genes together decreased resistance to oxidative stress and deletion of the antitoxin genes increased early biofilm formation. Collectively, these results demonstrated that the homologous Type IV TA systems in may target cell division protein FtsZ in and may have different physiological functions in .
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http://dx.doi.org/10.3390/toxins9030077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371832PMC
March 2017

Characterization of the Deep-Sea Streptomyces sp. SCSIO 02999 Derived VapC/VapB Toxin-Antitoxin System in Escherichia coli.

Toxins (Basel) 2016 07 1;8(7). Epub 2016 Jul 1.

Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, Research Network for Applied Microbiology (RNAM) Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.

Toxin-antitoxin (TA) systems are small genetic elements that are ubiquitous in prokaryotes. Most studies on TA systems have focused on commensal and pathogenic bacteria; yet very few studies have focused on TAs in marine bacteria, especially those isolated from a deep sea environment. Here, we characterized a type II VapC/VapB TA system from the deep-sea derived Streptomyces sp. SCSIO 02999. The VapC (virulence-associated protein) protein belongs to the PIN (PilT N-terminal) superfamily. Overproduction of VapC strongly inhibited cell growth and resulted in a bleb-containing morphology in E. coli. The toxicity of VapC was neutralized through direct protein-protein interaction by a small protein antitoxin VapB encoded by a neighboring gene. Antitoxin VapB alone or the VapB/VapC complex negatively regulated the vapBC promoter activity. We further revealed that three conserved Asp residues in the PIN domain were essential for the toxic effect of VapC. Additionally, the VapC/VapB TA system stabilized plasmid in E. coli. Furthermore, VapC cross-activated transcription of several TA operons via a partially Lon-dependent mechanism in E. coli, and the activated toxins accumulated more preferentially than their antitoxin partners. Collectively, we identified and characterized a new deep sea TA system in the deep sea Streptomyces sp. and demonstrated that the VapC toxin in this system can cross-activate TA operons in E. coli.
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http://dx.doi.org/10.3390/toxins8070195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963828PMC
July 2016

Complete genome sequence of Vibrio alginolyticus ATCC 33787(T) isolated from seawater with three native megaplasmids.

Mar Genomics 2016 Aug 19;28:45-47. Epub 2016 May 19.

Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, the South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China. Electronic address:

Vibrio alginolyticus, an opportunistic pathogen, is commonly associated with vibriosis in fish and shellfish and can also cause superficial and ear infections in humans. V. alginolyticus ATCC 33787(T) was originally isolated from seawater and has been used as one of the type strains for exploring the virulence factors of marine bacteria and for developing vaccine against vibriosis. Here we sequenced and assembled the whole genome of this strain, and identified three megaplasmids and three Type VI secretion systems, thus providing useful information for the study of virulence factors and for the development of vaccine for Vibrio.
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http://dx.doi.org/10.1016/j.margen.2016.05.003DOI Listing
August 2016