Publications by authors named "Junying Ma"

56 Publications

Transcriptome Profiling Reveals the Effects of Nitric Oxide on the Growth and Physiological Characteristics of Watermelon under Aluminum Stress.

Genes (Basel) 2021 Oct 29;12(11). Epub 2021 Oct 29.

College of Horticulture, Sichuan Agricultural University, Chengdu 611130, China.

Excessive aluminum ions (Al) in acidic soil can have a toxic effect on watermelons, restricting plant growth and reducing yield and quality. In this study, we found that exogenous application of nitric oxide (NO) could increase the photochemical efficiency of watermelon leaves under aluminum stress by promoting closure of leaf stomata, reducing malondialdehyde and superoxide anion in leaves, and increasing POD and CAT activity. These findings showed that the exogenous application of NO improved the ability of watermelon to withstand aluminum stress. To further reveal the mitigation mechanism of NO on watermelons under aluminum stress, the differences following different types of treatments-normal growth, Al, and Al + NO-were shown using de novo sequencing of transcriptomes. In total, 511 differentially expressed genes (DEGs) were identified between the Al + NO and Al treatment groups. Significantly enriched biological processes included nitrogen metabolism, phenylpropane metabolism, and photosynthesis. We selected 23 genes related to antioxidant enzymes and phenylpropane metabolism for qRT-PCR validation. The results showed that after exogenous application of NO, the expression of genes encoding and increased, consistent with the results of the physiological indicators. The expression patterns of genes involved in phenylpropanoid metabolism were consistent with the transcriptome expression abundance. These results indicate that aluminum stress was involved in the inhibition of the photosynthetic pathway, and NO could activate the antioxidant enzyme defense system and phenylpropane metabolism to protect cells and scavenge reactive oxygen species. This study improves our current understanding by comprehensively analyzing the molecular mechanisms underlying NO-induced aluminum stress alleviation in watermelons.
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http://dx.doi.org/10.3390/genes12111735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622656PMC
October 2021

Prevalence of Echinococcus Species in Wild Foxes and Stray Dogs in Qinghai Province, China.

Am J Trop Med Hyg 2021 Nov 15. Epub 2021 Nov 15.

National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai, China.

Echinococcosis is a zoonotic parasitic disease that is highly endemic to the Qinghai province of China. Limited data are available on the prevalence of the causal pathogen, Echinococcus spp., in definitive hosts in this region. Thus, the aim of this study was to evaluate the prevalence of Echinococcus spp. in wild foxes and stray dogs in Qinghai province. Five hundred and twenty-eight feces from wild foxes and 277 from stray dogs were collected from 11 counties in the Golog, Yushu, and Haixi prefectures and screened for Echinococcus spp. using copro-DNA polymerase chain reaction (PCR). In total, 5.5% of wild foxes and 15.2% of stray dogs tested positive for Echinococcus spp. The prevalence rates of Echinococcus spp. in wild foxes in Golog, Yushu, and Haixi were 7.3%, 5.2%, and 1.9%, respectively. In stray dogs, these rates were 13.3%, 17.3%, and 0%, respectively. Sequencing analysis determined that Echinococcus multilocularis was the most prevalent species, occurring in 4.0% and 12.6% of wild foxes and stray dogs, respectively. Echinococcus shiquicus was observed in 1.5% of wild foxes and 0.7% of stray dogs. Echinococcus granulosus was observed only in wild dogs, with a prevalence rate of 1.8%. To our knowledge, this is the first report on the prevalence of E. shiquicus in dogs in Qinghai province. The current results improve our understanding of the transmission and dissemination of human echinococcosis and suggest that exposure to the eggs of E. multilocularis harbored by wild foxes and stray dogs may pose a great risk of alveolar echinococcosis to humans in Qinghai province.
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http://dx.doi.org/10.4269/ajtmh.21-0622DOI Listing
November 2021

Semi-Synthesis of Marine-Derived Ilamycin F Derivatives and Their Antitubercular Activities.

Front Chem 2021 29;9:774555. Epub 2021 Oct 29.

CAS 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 Sciences, Guangzhou, China.

Tuberculosis (TB) is still a global disease threatening people's lives. With the emergence of multi-drug-resistant the prevention and control of tuberculosis faces new challenges, and the burden of tuberculosis treatment is increasing among the world. Ilamycins are novel cyclopeptides with potent anti-TB activities, which have a unique target protein against and drug-resistant strains. Herein, ilamycin F, a major secondary metabolite isolated from the marine-derived mutant strain SCSIO ZH16 Δ, is used as a scaffold to semi-synthesize eighteen new ilamycin derivatives (ilamycin NJL1-NJL18, -). Our study reveals that four of ilamycin NJLs (, and ) have slightly stronger anti-TB activities against H37Rv (minimum inhibitory concentration, 1.6-1.7 μM) compared with that of ilamycin F on day 14th, but obviously display more potent activities than ilamycin F on day 3rd, indicating anti-TB activities of these derivatives with fast-onset effect. In addition, cytotoxic assays show most ilamycin NJLs with low cytotoxicity except ilamycin NJL1 (). These findings will promote the further exploration of structure-activity relationships for ilamycins and the development of anti-TB drugs.
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http://dx.doi.org/10.3389/fchem.2021.774555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586704PMC
October 2021

Reducing Canine Echinococcus Infection with Smart Deworming Collars - Tibet, China, June-November, 2020.

China CDC Wkly 2020 Dec;2(51):979-982

National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health; National Center for International Research on Tropical Diseases; WHO Collaborating Centre for Tropical Diseases, Shanghai, China.

Existing manual deworming programs launched have made great progress in reducing the infection rate of domestic dogs, but significant challenges remain in scattered nomadic communities inhabiting the Tibetan Plateau. The low deworming frequency and low levels of coverage were responsible for the high infection rate of spp. among dogs.



Smart deworming collars controlled by a remote management system (RMS) was found to increase the deworming frequency and coverage and subsequently reduce the canine infection rates with spp..



As an innovative tool, smart deworming collars may drive the paradigm shift from manual deworming to smart deworming and stop the transmission of echinococcosis.
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http://dx.doi.org/10.46234/ccdcw2020.265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393154PMC
December 2020

Identification of risk factors for the prognosis of Chinese patients with endometrial carcinoma.

Medicine (Baltimore) 2021 Sep;100(38):e27305

Department of Obstetrics and Gynecology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China.

Abstract: This study aimed to retrospectively analyze risk factors for the prognosis of Chinese patients with endometrial carcinoma.Total 600 patients who were admitted to the Department of Gynecology, the Fourth Hospital of Hebei Medical University and were pathologically diagnosed as endometrial carcinoma after surgery from January 1, 1997 to December 31, 2006 were selected, and the related factors affecting their prognosis were analyzed.The survival of 600 patients with endometrial carcinoma was 2 to 136.5 months (average survival 57.39 ± 33.55 months), and 109 cases (18.2%) died from endometrial cancer. The overall survival rate of 1, 3, and 5 years after surgery was 96.8%, 89.9%, and 82.1%, respectively. Univariate analysis showed that age, menopausal status, pathological type, histological grade, pathological staging, tumor size, myometrial invasion, cervical involvement, ovarian metastasis, lymph node metastasis, and treatment method were the factors affecting the prognosis of endometrial carcinoma. Multivariate regression analysis showed that pathological type, histological grade, pathological staging, and cervical involvement were independent risk factors for the prognosis of endometrial carcinoma. The patients with high-grade and deep myometrial invasion, cervical involvement, full cavity tumor, and lymph node metastasis had a high incidence of ovarian metastasis.Pathological type, histological grade, pathological staging, and cervical involvement are independent risk factors affecting the prognosis of Chinese patients with endometrial carcinoma.
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http://dx.doi.org/10.1097/MD.0000000000027305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462610PMC
September 2021

Mutasynthesis of Antibacterial Halogenated Actinomycin Analogues.

J Nat Prod 2021 08 16;84(8):2217-2225. Epub 2021 Jul 16.

CAS 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 Sciences, Guangzhou 510301, People's Republic of China.

Through precursor-directed biosynthesis, feeding halogenated (F-, Cl-, Br-, I-) or methoxy-substituted 4-methyl-3-hydroxyanthranilic acid (4-MHA) analogues to the -deleted mutant strain of SCSIO ZS0073 led to the production of ten new actinomycin analogues (-). Several of the actinomycin congeners displayed impressive antimicrobial activities, with MIC values spanning 0.06-64 μg/mL to clinically derived antibiotic resistant pathogens, including , , and , with low cytotoxicity.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00294DOI Listing
August 2021

The correlations between Th1 and Th2 cytokines in human alveolar echinococcosis.

BMC Infect Dis 2020 Jun 15;20(1):414. Epub 2020 Jun 15.

Qinghai Institute for Endemic Disease Prevention and Control, Xining, 811602, Qinghai Province, China.

Background: Alveolar echinococcosis (AE) is a zoonotic parasitic disease caused by Echinococcus multilocularis larval tapeworm infections in humans that severely impairs the health of affected patients in the northern hemisphere.

Methods: The expression levels of 20 cytokines associated with AE infection were measured by enzyme-linked immunosorbent assay, and the correlations between these cytokines were analysed in the R programming language.

Results: Serum cytokine levels differed among individuals in both the AE patient and healthy control groups. The results of the correlations among the cytokines showed obvious differences between the two groups. In the AE patients group, Th1 and Th2 cytokines formed a more complicated network than that in the healthy control group.

Conclusions: The altered correlations between Th1 and Th2 cytokines may be closely associated with AE infection, which may provide a new explanation for the essential differences between AE patients and healthy individuals.
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http://dx.doi.org/10.1186/s12879-020-05135-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294603PMC
June 2020

Production of Antitubercular Depsipeptides via Biosynthetic Engineering of Cinnamoyl Units.

J Nat Prod 2020 05 27;83(5):1666-1673. Epub 2020 Apr 27.

CAS 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 Sciences, Guangzhou 510301, People's Republic of China.

Two new cyclodecapeptides, atratumycins B () and C (), containing substituted cinnamoyl side chains were generated by converging elements of the atratumycin () and atrovimycin () biosynthetic pathways. The structures of and were determined on the basis of HRESIMS, 1D and 2D NMR data, and X-ray single-crystal diffraction studies. Atratumycin B () is active against autoluminescent H37Rv, displaying a minimum inhibitory concentration of 3.1 μg/mL (2.3 μM).
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http://dx.doi.org/10.1021/acs.jnatprod.0c00194DOI Listing
May 2020

Antitubercular Ilamycins from Marine-Derived SCSIO ZH16 Δ.

J Nat Prod 2020 05 23;83(5):1646-1657. Epub 2020 Apr 23.

CAS 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 Sciences, 164 West Xingang Road, Guangzhou 510301, China.

Tuberculosis (TB) ranks as the leading cause of death from a single infectious agent (ranking more lethal than HIV/AIDS) over the course of the past decade. More concerning is that reports of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of TB have been dramatically increasing. It continues to become ever more clear that novel anti-TB drugs with improved efficacies and reduced toxicities are urgently needed. We report here the discovery of 12 new ilamycin analogues, ilamycins G-R (-), bearing various nonproteinogenic amino acids, along with ilamycins E () and F (), from a 200 L scale culture of the marine-derived mutant actinomycete SCSIO ZH16 Δ. Importantly, bioassays against H37Rv revealed that all 12 new agents displayed antitubercular activities with MIC values ranging from 0.0096 to 10 μM. The structures of - were elucidated on the basis of HRESIMS, 1D and 2D NMR, and X-ray single-crystal diffraction studies. In addition, compound was found to be moderately cytotoxic against a panel of tumor human cell lines. From these data we can formulate tentative structure-activity relationships for the antitubercular and antitumor activities of the ilamycins.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00151DOI Listing
May 2020

Characterization of Regulatory and Transporter Genes in the Biosynthesis of Anti-Tuberculosis Ilamycins and Production in a Heterologous Host.

Mar Drugs 2020 Apr 17;18(4). Epub 2020 Apr 17.

CAS 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 Sciences, Guangzhou 510301, China.

Ilamycins are cyclopeptides with novel structures that have been isolated from different . They showed strong anti-tuberculosis activity and could serve as important anti-tuberculosis drug leads. The functions of the pre-tailoring and the post-tailoring genes in the biosynthesis of ilamycins have been elucidated, but the functions of the regulatory and transporter genes remain elusive. We reported herein the functions of four genes in ilamycin biosynthetic gene cluster ( BGC) including two regulatory genes ( and ) and two transporter genes ( and ) and the heterologous expression of BGC. The IlaA and IlaB were unambiguously shown to be negative and positive regulator of ilamycins biosynthesis, respectively. Consistent with these roles, inactivation of and (independent of each other) was shown to enhance and abolish the production of ilamycins, respectively. Total yields of ilamycins were enhanced 3.0-fold and 1.9-fold by inactivation of and overexpression of compared to those of in the SCSIO ZH16, respectively. In addition, the BGC was successfully expressed in M1152, which indicated that all biosynthetic elements for the construction of ilamycins were included in the PAC7A6. These results not only lay a foundation for further exploration of ilamycins, but also provide the genetic elements for synthetic biology.
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http://dx.doi.org/10.3390/md18040216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230496PMC
April 2020

National Alveolar Echinococcosis Distribution - China, 2012-2016.

China CDC Wkly 2020 Jan;2(1):1-7

National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Chinese Center for Tropical Diseases Research; WHO Collaborating Centre for Tropical Diseases; National Center for International Research on Tropical Diseases, Ministry of Science and Technology; Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, China.

Both alveolar echinococcosis (AE) and cystic echinococcosis are endemic in China, among which alveolar echinococcosis has a very high mortality rate.



The survey results showed the prevalence and scope of AE in China and identified high-risk groups including children, monks, herdsmen and illiterate people. At the same time, all the cases found in the survey (more than 90% of the patients did not go to the hospital for diagnosis and treatment before survey) were promptly diagnosed and treated.



This study provides information for the development of a plan for AE prevention and control and for the implementation of interventions targeted to high-risk populations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422174PMC
January 2020

CytA, a reductase in the cytorhodin biosynthesis pathway, inactivates anthracycline drugs in .

Commun Biol 2019 6;2:454. Epub 2019 Dec 6.

1CAS 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 Sciences, Guangzhou, 510301 China.

Antibiotic-producing microorganism can develop strategies to deal with self-toxicity. Cytorhodins X and Y, cosmomycins A and B, and iremycin, are produced as final products from a marine-derived sp. SCSIO 1666. These C-7 reduced metabolites show reduced antimicrobial and comparable cytotoxic activities relative to their C-7 glycosylated counterparts. However, the biosynthetic mechanisms and relevant enzymes that drive C-7 reduction in cytorhodin biosynthesis have not yet been characterized. Here we report the discovery and characterization of a reductase, CytA, that mediates C-7 reduction of this anthracycline scaffold; CytA endows the producer sp. SCSIO 1666 with a means of protecting itself from the effects of its anthracycline products. Additionally, we identified cosmomycins C and D as two intermediates involved in cytorhodin biosynthesis and we also broadened the substrate specificity of CytA to clinically used anthracycline drugs.
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http://dx.doi.org/10.1038/s42003-019-0699-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897945PMC
July 2020

Exploration and genome mining of natural products from marine Streptomyces.

Appl Microbiol Biotechnol 2020 Jan 26;104(1):67-76. Epub 2019 Nov 26.

CAS 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 Sciences, Guangzhou, 510301, China.

Marine Streptomyces sp. are an important source of bioactive compounds owing to their unique habitats and metabolic pathways. Whole-genome sequencing and bioinformatics analyses have shown that the potential of synthesizing secondary metabolites from marine-derived Streptomyces has been substantially underestimated. Genome mining is an integrated strategy used to discover natural products based on gene cluster sequences and biosynthetic pathways. Its emergence has greatly enhanced the discovery of natural compounds from marine Streptomyces, thereby yielding a large number of bioactive molecules with novel structures and potent activities. In this review, we briefly summarize the current applications of genome mining in marine Streptomyces, such as bioinformatics-based optimization of culture conditions, ribosome engineering, control of regulatory networks, heterologous expression of biosynthetic gene cluster, and combinatorial biosynthesis of natural compounds. Furthermore, we discuss the factors hindering the utilization of marine-derived natural products and conclude with the prospects for this technique.
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http://dx.doi.org/10.1007/s00253-019-10227-0DOI Listing
January 2020

Characterization of the Noncanonical Regulatory and Transporter Genes in Atratumycin Biosynthesis and Production in a Heterologous Host.

Mar Drugs 2019 Sep 29;17(10). Epub 2019 Sep 29.

CAS 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 Sciences, Guangzhou 510301, China.

Atratumycin is a cyclodepsipeptide with activity against isolated from deep-sea derived SCSIO ZH16NS-80S. Analysis of the atratumycin biosynthetic gene cluster () revealed that its biosynthesis is regulated by multiple factors, including two LuxR regulatory genes ( and ), two ABC transporter genes ( and ) and one antibiotic regulatory gene (). In this work, three regulatory and two transporter genes were unambiguously determined to provide positive, negative and self-protective roles during biosynthesis of atratumycin through bioinformatic analyses, gene inactivations and -complementation studies. Notably, an unusual antibiotic regulatory protein Atr32 was characterized as a negative regulator; the function of Atr32 is distinct from previous studies. Five over-expression mutant strains were constructed by rational application of the regulatory and transporter genes; the resulting strains produced significantly improved titers of atratumycin that were ca. 1.7-2.3 fold greater than wild-type (WT) producer. Furthermore, the atratumycin gene cluster was successfully expressed in M1154, thus paving the way for the transfer and recombination of large DNA fragments. Overall, this finding sets the stage for understanding the unique biosynthesis of pharmaceutically important atratumycin and lays the foundation for generating anti-tuberculosis lead compounds possessing novel structures.
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http://dx.doi.org/10.3390/md17100560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835768PMC
September 2019

Ilamycin E, a natural product of marine actinomycete, inhibits triple-negative breast cancer partially through ER stress-CHOP-Bcl-2.

Int J Biol Sci 2019 10;15(8):1723-1732. Epub 2019 Jun 10.

Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China, 650223.

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women in the worldwide. Triple-negative breast cancer (TNBC) has a poor clinical outcome. The antitumor efficacy of Ilamycins, natural products with anti-tuberculosis activity isolated from deep sea-derived Streptomyces atratus, in TNBC has not been investigated, and the mechanisms remain elusive. Here, we demonstrated that Ilamycin-E, but not -F, decreases cell viability, inhibits G1/S cell cycle progression, and promotes apoptosis in the TNBC cell lines HCC1937 and MDA-MB-468. Ilamycin E promotes apoptosis via activation of endoplasmic reticulum (ER) stress, increasing the expression of CHOP, and down-regulating the expression of anti-apoptotic protein Bcl-2. Depletion of CHOP or overexpression of Bcl2 significantly rescued Ilamycin E-induced apoptosis. These findings indicate that Ilamycin E has anti-cancer activity in TNBC.
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http://dx.doi.org/10.7150/ijbs.35284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643221PMC
April 2020

Ilamycin C induces apoptosis and inhibits migration and invasion in triple-negative breast cancer by suppressing IL-6/STAT3 pathway.

J Hematol Oncol 2019 06 11;12(1):60. Epub 2019 Jun 11.

CAS 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 Sciences, Guangzhou, 510301, China.

Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis, and its treatment remains a challenge due to few targeted medicines and high risk of relapse, metastasis, and drug resistance. Thus, more effective drugs and new regimens for the therapy of TNBC are urgently needed. Ilamycins are a kind of cyclic peptides and produced by Streptomyces atratus and Streptomyces islandicus with effective anti-tuberculosis activity. Ilamycin C is a novel compound isolated from the deep South China Sea-derived Streptomyces atratus SCSIO ZH16 and exhibited a strong cytotoxic activity against several cancers including breast cancer cell line MCF7. However, the cytotoxic activity of Ilamycin C to TNBC cells and a detailed antitumor mechanism have not been reported.

Methods: CCK-8 assays were used to examine cell viability and cytotoxic activity of Ilamycin C to TNBC, non-TNBC MCF7, and nonmalignant MCF10A cells. EdU assays and flow cytometry were performed to assess cell proliferation and cell apoptosis. Transwell migration and Matrigel invasion assays were utilized to assess the migratory and invading capacity of TNBC cells following the treatment of Ilamycin C. The expressions of proteins were detected by western blot.

Results: In this study, we found that Ilamycin C has more preferential cytotoxicity in TNBC cells than non-TNBC MCF7 and nonmalignant MCF10A cells. Notably, our studies revealed the mechanism that Ilamycin C can induce Bax/Bcl-2-related caspase-dependent apoptosis and inhibit migration and invasion through MMP2/MMP9/vimentin/fascin in TNBC by suppressing IL-6-induced STAT3 phosphorylation.

Conclusions: This study provides the first evidence that Ilamycin C has significant implications for the potential as a novel IL-6/STAT3 inhibitor for TNBC treatment in the future.
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http://dx.doi.org/10.1186/s13045-019-0744-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558915PMC
June 2019

Identification of the Actinomycin D Biosynthetic Pathway from Marine-Derived SCSIO ZS0073.

Mar Drugs 2019 Apr 23;17(4). Epub 2019 Apr 23.

CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, 164 West Xingang Road, Guangzhou 510301, China.

Bioactive secondary metabolites from are important sources of lead compounds in current drug development. SCSIO ZS0073, a mangrove-derived actinomycete, produces actinomycin D, a clinically used therapeutic for Wilm's tumor of the kidney, trophoblastic tumors and rhabdomyosarcoma. In this work, we identified the actinomycin biosynthetic gene cluster (BGC) by detailed analyses of the SCSIO ZS0073 genome. This organism produces actinomycin D with a titer of ~69.8 μg mL along with traces of actinomycin X. The cluster localized to a 39.8 kb length region consisting of 25 open reading frames (ORFs), including a set of four genes that drive the construction of the 4-methyl-3-hydroxy-anthranilic acid (4-MHA) precursor and three non-ribosomal peptide synthetases (NRPSs) that generate the 4-MHA pentapeptide semi-lactone, which, upon dimerization, affords final actinomycin D. Furthermore, the cluster contains four positive regulatory genes , which were identified by in vivo gene inactivation studies. Our data provide insights into the genetic characteristics of this new mangrove-derived actinomycin D bioproducer, enabling future metabolic engineering campaigns to improve both titers and the structural diversities possible for actinomycin D and related analogues.
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http://dx.doi.org/10.3390/md17040240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521150PMC
April 2019

Discovery and Biosynthesis of Atrovimycin, an Antitubercular and Antifungal Cyclodepsipeptide Featuring Vicinal-dihydroxylated Cinnamic Acyl Chain.

Org Lett 2019 04 8;21(8):2634-2638. Epub 2019 Apr 8.

CAS 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 Sciences , Guangzhou 510301 , China.

Atrovimycin (1), a cyclodepsipeptide containing a unique vicinal-hydroxylated cinnamic acyl chain, was isolated and elucidated from Streptomyces atrovirens LQ13. The biosynthetic pathway of 1 was achieved, revealing cytochrome P450 (Avm43) and epoxide hydrolase (Avm29) enzymes constructing the vicinal-dihydroxy substitution, as well as a tailoring P450 (Avm28) enzyme catalyzing β-hydroxylation of the l-Phe moiety. Atrovimycin shows in vitro antifungal activity and antitubercular activity against Mycobacterium tuberculosis H37Rv both in vitro (with MIC of 2.5 μg/mL) and in vivo.
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http://dx.doi.org/10.1021/acs.orglett.9b00618DOI Listing
April 2019

Genome Mining of Streptomyces atratus SCSIO ZH16: Discovery of Atratumycin and Identification of Its Biosynthetic Gene Cluster.

Org Lett 2019 03 12;21(5):1453-1457. Epub 2019 Feb 12.

CAS 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 Sciences , Guangzhou 510301 , China.

Genome mining of the deep sea-derived Streptomyces atratus SCSIO ZH16 enabled the activation of a cyclodepsipeptide gene cluster and isolation of its cinnamic acid-bearing product, atratumycin (1). Atratumycin's structure was elucidated on the basis of extensive spectroscopic experiments, X-ray data, and Marfey's method; a plausible biosynthesis and tailoring modification of 1 are also proposed and investigated. Additionally, atratumycin is active against Mycobacteria tuberculosis H37Ra and H37Rv with MICs of 3.8 and 14.6 μM, respectively.
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http://dx.doi.org/10.1021/acs.orglett.9b00208DOI Listing
March 2019

Enhancement of himastatin bioproduction via inactivation of atypical repressors in .

Metab Eng Commun 2019 Jun 5;8:e00084. Epub 2019 Jan 5.

CAS Key Laboratory of Tropical Marine Bioresources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, Research Network for Applied Microbiology Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.

Three atypical regulatory genes, have been discovered within the himastatin biosynthetic gene cluster (BGC) in ATCC 53653 and the roles of their products have been identified. HmtA and HmtD do not show any structurally distinct features characteristic of regulatory function yet were shown to play important repressive and stimulatory roles, respectively, related to himastatin biosynthesis. HmtB encodes a conserved acetylglutamate kinase; new member of this family serves as repressor of secondary metabolism. Through repressive networks engineering, the limiting functions of HmtA and HmtB along with the activating functions of HmtD in the himastatin BGC have been identified for the first time by gene activation, qPCR, RT-PCR and HPLC studies of selected mutant strains; two of these mutant strains (Δ and Δ) produced himastatin in titers (19.02 ± 1.2 μg/mL, 9.9 folds and 30.40 ± 0.83 μg/mL, 15.8 folds) far exceeding those of the wild-type (WT) producer. Overall, this work provides significant insight into secondary metabolic regulatory mechanisms in . These efforts also highlight and validate a new strategy enabling expanded exploitation of cyclopeptidic natural products such as himastatin that demonstrate exciting antimicrobial and antitumor potentials.
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http://dx.doi.org/10.1016/j.mec.2018.e00084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328088PMC
June 2019

Genome Mining for Mycemycin: Discovery and Elucidation of Related Methylation and Chlorination Biosynthetic Chemistries.

Org Lett 2018 12 26;20(23):7633-7636. Epub 2018 Nov 26.

CAS 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 Sciences , 164 West Xingang Road , Guangzhou 510301 , China.

A silent dibenzoxazepinone (DBP) biosynthetic gene cluster ( myc) was mutagenically activated in Streptomyces olivaceus SCSIO T05, enabling the discovery of mycemycin C (4) and three new analogues [mycemycins F-H (1-3)]. Gene disruption, complementation experiments, and enzymatic assays unveiled salicylic acid and 5-Cl-kynurenine as biosynthetic precursors and shed significant functional insights into MycO, MycB, MycR, and MycJ, enzymes responsible for fine-tuning of the DBP scaffold.
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http://dx.doi.org/10.1021/acs.orglett.8b03373DOI Listing
December 2018

Genome Sequencing of SCSIOZH16 and Activation Production of Nocardamine via Metabolic Engineering.

Front Microbiol 2018 13;9:1269. Epub 2018 Jun 13.

CAS 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 Sciences, Guangzhou, China.

The are metabolically flexible microorganisms capable of producing a wide range of interesting compounds, including but by no means limited to, siderophores which have high affinity for ferric iron. In this study, we report the complete genome sequence of marine-derived ZH16 and the activation of an embedded siderophore gene cluster via the application of metabolic engineering methods. The ZH16 genome reveals that this strain has the potential to produce 26 categories of natural products (NPs) barring the ilamycins. Our activation studies revealed SCSIO ZH16 to be a promising source of the production of nocardamine-type (desferrioxamine) compounds which are important in treating acute iron intoxication and performing ecological remediation. We conclude that metabolic engineering provides a highly effective strategy by which to discover drug-like compounds and new NPs in the genomic era.
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http://dx.doi.org/10.3389/fmicb.2018.01269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011815PMC
June 2018

Enzymatic Synthesis of GDP-α-l-fucofuranose by MtdL and Hyg20.

Org Lett 2018 02 30;20(4):1015-1018. Epub 2018 Jan 30.

CAS 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 Sciences , 164 West Xingang Road, Guangzhou 510301, China.

Two mutases, MtdL and Hyg20, are reported. Both are able to functionally drive the biosynthesis of GDP-α-l-fucofuranose. Both enzymes catalyze similar functions, catalytically enabling the bidirectional reaction between GDP-β-l-fucopyranose and GDP-α-l-fucofuranose using only divalent cations as cofactors. This realization is but one of a number of important insights into fucofuranose biosynthesis presented herein.
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http://dx.doi.org/10.1021/acs.orglett.7b03962DOI Listing
February 2018

Identification and utilization of two important transporters: SgvT1 and SgvT2, for griseoviridin and viridogrisein biosynthesis in Streptomyces griseoviridis.

Microb Cell Fact 2017 Oct 25;16(1):177. Epub 2017 Oct 25.

CAS Key Laboratory of Tropical Marine Bioresources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, Research Network for Applied Microbiology Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, China.

Background: Griseoviridin (GV) and viridogrisein (VG, also referred as etamycin), both biosynthesized by a distinct 105 kb biosynthetic gene cluster (BGC) in Streptomyces griseoviridis NRRL 2427, are a pair of synergistic streptogramin antibiotics and very important in treating infections of many multi-drug resistant microorganisms. Three transporter genes, sgvT1-T3 have been discovered within the 105 kb GV/VG BGC, but the function of these efflux transporters have not been identified.

Results: In the present study, we have identified the different roles of these three transporters, SgvT1, SgvT2 and SgvT3. SgvT1 is a major facilitator superfamily (MFS) transporter whereas SgvT2 appears to serve as the sole ATP-binding cassette (ABC) transporter within the GV/VG BGC. Both proteins are necessary for efficient GV/VG biosynthesis although SgvT1 plays an especially critical role by averting undesired intracellular GV/VG accumulation during biosynthesis. SgvT3 is an alternative MFS-based transporter that appears to serve as a compensatory transporter in GV/VG biosynthesis. We also have identified the γ-butyrolactone (GBL) signaling pathway as a central regulator of sgvT1-T3 expression. Above all, overexpression of sgvT1 and sgvT2 enhances transmembrane transport leading to steady production of GV/VG in titers ≈ 3-fold greater than seen for the wild-type producer and without any notable disturbances to GV/VG biosynthetic gene expression or antibiotic control.

Conclusions: Our results shows that SgvT1-T2 are essential and useful in GV/VG biosynthesis and our effort highlight a new and effective strategy by which to better exploit streptogramin-based natural products of which GV and VG are prime examples with clinical potential.
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http://dx.doi.org/10.1186/s12934-017-0792-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655939PMC
October 2017

Biosynthesis of ilamycins featuring unusual building blocks and engineered production of enhanced anti-tuberculosis agents.

Nat Commun 2017 08 30;8(1):391. Epub 2017 Aug 30.

CAS 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 Sciences, Guangzhou, 510301, China.

Tuberculosis remains one of the world's deadliest communicable diseases, novel anti-tuberculosis agents are urgently needed due to severe drug resistance and the co-epidemic of tuberculosis/human immunodeficiency virus. Here, we show the isolation of six anti-mycobacterial ilamycin congeners (1-6) bearing rare L-3-nitro-tyrosine and L-2-amino-4-hexenoic acid structural units from the deep sea-derived Streptomyces atratus SCSIO ZH16. The biosynthesis of the rare L-3-nitrotyrosine and L-2-amino-4-hexenoic acid units as well as three pre-tailoring and two post-tailoring steps are probed in the ilamycin biosynthetic machinery through a series of gene inactivation, precursor chemical complementation, isotope-labeled precursor feeding experiments, as well as structural elucidation of three intermediates (6-8) from the respective mutants. Most impressively, ilamycins E/E, which are produced in high titers by a genetically engineered mutant strain, show very potent anti-tuberculosis activity with an minimum inhibitory concentration value ≈9.8 nM to Mycobacterium tuberculosis H37Rv constituting extremely potent and exciting anti-tuberculosis drug leads.Tuberculosis (TB) remains one of the world's deadliest communicable diseases, novel anti-TB agents are urgently needed due to severe drug resistance and the co-epidemic of TB/HIV. Here, the authors show that anti-mycobacterial ilamycin congeners bearing unusual structural units possess extremely potent anti-tuberculosis activities.
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http://dx.doi.org/10.1038/s41467-017-00419-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577134PMC
August 2017

Base-Mediated Cascade Substitution-Cyclization of 2H-Azirines: Access to Highly Substituted Oxazoles.

Org Lett 2017 07 13;19(13):3370-3373. Epub 2017 Jun 13.

School of Chemical Engineering & Pharmaceutics, Henan University of Science and Technology , Luoyang 471003, Henan, China.

A novel strategy to synthesize highly functionalized oxazoles has been successfully developed via a base-mediated intermolecular substitution between 2-acyloxy-2H-azirines and N-nucleophile or O-nucleophile with a subsequent ring expansion of a 2H-azirine intermediate. This method provides straightforward access to highly substituted oxazoles with high efficiency and excellent functional group compatibility under metal-free reaction conditions.
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http://dx.doi.org/10.1021/acs.orglett.7b01305DOI Listing
July 2017

Deciphering the sugar biosynthetic pathway and tailoring steps of nucleoside antibiotic A201A unveils a GDP-l-galactose mutase.

Proc Natl Acad Sci U S A 2017 05 24;114(19):4948-4953. Epub 2017 Apr 24.

Chinese Academy of Sciences (CAS) Key Laboratory of Tropical Marine Bioresources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, Research Network for Applied Microbiology Center for Marine Microbiology, South China Sea Institute of Oceanology, CAS, Guangzhou 510301, China;

Galactose, a monosaccharide capable of assuming two possible configurational isomers (d-/l-), can exist as a six-membered ring, galactopyranose (Gal), or as a five-membered ring, galactofuranose (Gal). UDP-galactopyranose mutase (UGM) mediates the conversion of pyranose to furanose thereby providing a precursor for d-Gal Moreover, UGM is critical to the virulence of numerous eukaryotic and prokaryotic human pathogens and thus represents an excellent antimicrobial drug target. However, the biosynthetic mechanism and relevant enzymes that drive l-Gal production have not yet been characterized. Herein we report that efforts to decipher the sugar biosynthetic pathway and tailoring steps en route to nucleoside antibiotic A201A led to the discovery of a GDP-l-galactose mutase, MtdL. Systematic inactivation of 18 of the 33 biosynthetic genes in the A201A cluster and elucidation of 10 congeners, coupled with feeding and in vitro biochemical experiments, enabled us to: () decipher the unique enzyme, GDP-l-galactose mutase associated with production of two unique d-mannose-derived sugars, and () assign two glycosyltransferases, four methyltransferases, and one desaturase that regiospecifically tailor the A201A scaffold and display relaxed substrate specificities. Taken together, these data provide important insight into the origin of l-Gal-containing natural product biosynthetic pathways with likely ramifications in other organisms and possible antimicrobial drug targeting strategies.
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http://dx.doi.org/10.1073/pnas.1620191114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441726PMC
May 2017

Epidemiology of Echinococcosis Among Schoolchildren in Golog Tibetan Autonomous Prefecture, Qinghai, China.

Am J Trop Med Hyg 2017 03 6;96(3):674-679. Epub 2017 Apr 6.

National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Key Laboratory of Parasite and Vector Biology, Ministry of Health, WHO Collaborating Center of Malaria, Schistosomiasis and Filariasis, Shanghai, China.

Echinococcosis is a serious zoonotic parasitic disease that is highly endemic in Qinghai Province. The present study aimed to investigate the prevalence of echinococcosis among schoolchildren in Golog Tibetan Autonomous Prefecture to improve early diagnosis and treatment of patients and to provide information for echinococcosis prevention and control. A total of 11,260 schoolchildren from five counties (Maqin, Gander, Dari, Jiuzhi, and Banma) in Golog Tibetan Autonomous Prefecture, Qinghai Province, were screened for echinococcosis. Screening involved ultrasound imaging combined with serologic examination as an auxiliary diagnostic test. The prevalence of echinococcosis in the schoolchildren was 2.1% (235/11,260), with a rate of 0.8% for cystic echinococcosis (CE; 89/11,260) and 1.3% for alveolar echinococcosis (AE; 146/11,260). Additionally, one child had a mixed infection. The prevalence ranged between 1.1% and 4.1% among the five investigated counties, and was highest in Dari County (4.1%). The prevalence of echinococcosis was higher in girls than in boys and gradually increased with age. In addition, children with CE mainly had type 1 (CE1) and type 3 (CE3) lesions, and children with AE mainly had small-diameter calcified lesions, suggesting that they were in the early asymptomatic stage of echinococcosis. In conclusion, children of Golog Tibetan Autonomous Prefecture appear to exhibit the highest recorded prevalence of CE and AE globally. Ultrasound is useful for screening populations in regions where both CE and AE are endemic.
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http://dx.doi.org/10.4269/ajtmh.16-0479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361544PMC
March 2017

P57 and cyclin G1 express differentially in proliferative phase endometrium and early pregnancy decidua.

Int J Clin Exp Med 2015 15;8(4):5144-9. Epub 2015 Apr 15.

Reproductive Medicine Center, Tongji Medicine College, Tongji Hospital, Huazhong University of Science and Technology Wuhan, China.

Objective: To compare the expression of P57 and Cyclin G1 in proliferation endometrium and early pregnancy decidua.

Methods: Human endometrial samples were acquired from normal menstrual cycle women undergoing laparoscopy or hysterectomy for fallopian tubes problems. Decidua were acquired from women in early pregnancy who underwent artificial abortion without any endometrial problems. Twelve were in proliferative phase and 13 were deciduas. P57 and Cyclin G1 mRNA and protein were measured by real-time PCR and Western blot.

Results: The expression of P57 mRNA and protein were lower in proliferation phase compared with the early pregnancy decidua. Cyclin G1 mRNA and protein expression were slightly higher in decidua than proliferation endometrium but it had no significant difference.

Conclusion: P57 and Cyclin G1 may play an important role in the endometrial change during the embryo implantation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483989PMC
July 2015

Discovery of a new family of Dieckmann cyclases essential to tetramic acid and pyridone-based natural products biosynthesis.

Org Lett 2015 Feb 26;17(3):628-31. Epub 2015 Jan 26.

CAS 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 Sciences , 164 West Xingang Road, Guangzhou 510301, China.

Bioinformatic analyses indicate that TrdC, SlgL, LipX2, KirHI, and FacHI belong to a group of highly homologous proteins involved in biosynthesis of actinomycete-derived tirandamycin B, streptolydigin, α-lipomycin, kirromycin, and factumycin, respectively. However, assignment of their biosynthetic roles has remained elusive. Gene inactivation and complementation, in vitro biochemical assays with synthetic analogues, point mutations, and phylogenetic tree analyses reveal that these proteins represent a new family of Dieckmann cyclases that drive tetramic acid and pyridone scaffold biosynthesis.
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http://dx.doi.org/10.1021/ol5036497DOI Listing
February 2015
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