Publications by authors named "Lingyan Liu"

74 Publications

Combustion-Derived Particulate PAHs Associated with Small Airway Dysfunction in Elderly Patients with COPD.

Environ Sci Technol 2022 Aug 14;56(15):10868-10878. Epub 2022 Jul 14.

Department of Occupational and Environmental Health, Peking University School of Public Health, No. 38 Xueyuan Road, Haidian District, Beijing 100191, China.

Evidence of the respiratory effects of ambient organic aerosols (e.g., polycyclic aromatic hydrocarbons, PAHs) among patients with chronic diseases is limited. We aimed to assess whether exposure to ambient particle-bound PAHs could worsen small airway functions in patients with chronic obstructive pulmonary disease (COPD) and elucidate the underlying mechanisms involved. Forty-five COPD patients were recruited with four repeated visits in 2014-2015 in Beijing, China. Parameters of pulmonary function and pulmonary/systemic inflammation and oxidative stress were measured at each visit. Linear mixed-effect models were performed to evaluate the associations between PAHs and measurements. In this study, participants experienced an average PAH level of 61.7 ng/m. Interquartile range increases in exposure to particulate PAHs at prior up to 7 days were associated with reduced small airway functions, namely, decreases of 17.7-35.5% in forced maximal mid-expiratory flow. Higher levels of particulate PAHs were also associated with heightened lung injury and inflammation and oxidative stress. Stronger overall effects were found for PAHs from traffic emissions and coal burning. Exposure to ambient particulate PAHs was capable of impairing small airway functions in elderly patients with COPD, potentially via inflammation and oxidative stress. These findings highlight the importance of control efforts on organic particulate matter from fossil fuel combustion emissions.
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http://dx.doi.org/10.1021/acs.est.2c00797DOI Listing
August 2022

circEPSTI1 promotes tumor progression and cisplatin resistance via upregulating MSH2 in cervical cancer.

Aging (Albany NY) 2022 07 2;14(13):5406-5416. Epub 2022 Jul 2.

Department of Obstetrics and Gynecology, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong, China.

CircRNAs (circRNAs) are a kind of non-coding RNAs which are extensively distributed in tissues. Previous investigations reported that circRNAs harbor indispensable roles in modulating the progress of multiple cancers. Nevertheless, the function along with the molecular mechanism of most circRNAs in cervical cancer progression was still not clear. Herein, we illustrated that circEPSTI1 is a remarkably upregulated circRNA, which we validated in tissues with cervical cancer along with cell lines. The biological role of circEPSTI1 in the advancement of cervical cancer was probed via loss-of function assessments. Silencing circEPSTI1 could diminish the proliferative capacity of the cervical cancer cells to spread. In cervical cancer cells, silencing circEPSTI1 dramatically elevated drug responsivity to cisplatin. Mechanically, RNA immuno-precipitation experiments and dual luciferase enzyme reporter experiments were conducted to reveal the molecular mechanism of circEPSTI1 in cervical cancer. In conclusion, this research premise identified the biological function of circEPSTI1-miR-370-3p-MSH2 axis in cervical cancer progression. Our result is significant for slowing the progress of and overcoming drug resistance of cervical cancer.
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http://dx.doi.org/10.18632/aging.204152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320557PMC
July 2022

Hypochlorous acid triggered fluorescent probes for imaging of a psoriasis model.

J Mater Chem B 2022 07 13;10(27):5211-5217. Epub 2022 Jul 13.

State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China.

Psoriasis is a common skin disease with complex pathogenesis that lacks diagnostic methods. Typically, psoriasis is an inflammation-related disease accompanied by high expression of reactive oxygen species (ROS) in the infected part. However, due to the lack of suitable tools, it is difficult to identify the ROS, especially certain types of ROS (, HOCl) in the psoriasis model. Here, two HOCl-specific fluorescent probes, G1 and G2, were designed and synthesized based on oxazine 1. Both probes could react with HOCl with high selectivity among other ROS under physiological conditions. The selected probe G2 could detect HOCl in HL-60 cells without special stimulation and detect endogenously produced HOCl in the mouse model of arthritis. Thus, G2 was used to identify and image HOCl in the imiquimod induced psoriasis model. The result showed that HOCl was a potential pathological marker of psoriasis.
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http://dx.doi.org/10.1039/d2tb00765gDOI Listing
July 2022

Short-term exposure to traffic-related air pollution and STEMI events: Insights into STEMI onset and related cardiac impairment.

Sci Total Environ 2022 Jun 28;827:154210. Epub 2022 Feb 28.

Department of Occupational and Environmental Health, Peking University School of Public Health, Peking University Institute of Environmental Medicine, Beijing, China; Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Beijing, China. Electronic address:

Aims: Evidence on the impacts of traffic-related air pollution (TRAP) on ST-segment elevation myocardial infarction (STEMI) events is limited. We aimed to assess the acute effects of TRAP exposure on the clinical onset of STEMI and related cardiac impairments.

Methods And Results: We recruited patients who were admitted for STEMI and underwent primary percutaneous coronary intervention at Peking University Third Hospital between 2014 and 2020. Indicators relevant to cardiac impairments were measured. Concomitantly, hourly concentrations of traffic pollutants were monitored throughout the study period, including fine particulate matter, black carbon (BC), particles in size ranges of 5-560 nm, oxides of nitrogen (NO), nitrogen dioxide, and carbon monoxide. The mean (SD) age of participants was 62.4 (12.5) years. Daily average (range) concentrations of ambient BC and NO were 3.9 (0.1-25.0) μg/m and 90.8 (16.6-371.7) μg/m. Significant increases in STEMI risks of 5.9% (95% CI: 0.1, 12.0) to 21.9% (95% CI: 6.0, 40.2) were associated with interquartile range increases in exposure to TRAP within a few hours. These changes were accompanied by significant elevations in cardiac troponin T levels of 6.9% (95% CI: 0.2, 14.1) to 41.7% (95% CI: 21.2, 65.6), as well as reductions in left ventricular ejection fraction of 1.5% (95% CI: 0.1, 2.9) to 3.7% (95% CI: 0.8, 6.4). Furthermore, the associations were attenuated in participants living in areas with higher residential greenness levels.

Conclusions: Our findings extend current understanding that short-term exposure to higher levels of traffic pollution was associated with increased STEMI risks and exacerbated cardiac impairments, and provide evidence on traffic pollution control priority for protecting vulnerable populations who are at greater risks of cardiovascular events.
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http://dx.doi.org/10.1016/j.scitotenv.2022.154210DOI Listing
June 2022

A Smart Theranostic Prodrug System Activated by Reactive Oxygen Species for Regional Chemotherapy of Metastatic Cancer.

Angew Chem Int Ed Engl 2022 03 3;61(12):e202116807. Epub 2022 Feb 3.

State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, China.

Metastatic cancer is difficult to cure because of its uncontrollable nature and side effects during treatment. We constructed a reactive oxygen species (ROS)-activated smart theranostic prodrug system based on an ROS active site linked with both a targeting group and an anticancer drug for efficient regional chemotherapy of metastatic cancers. The optimized prodrug (Bio-(8)-MB-CPT) with biotin as the targeting group displayed high sensitivity towards ROS and selectively targeting ability towards cervical cancer cells, showing highly efficient drug release (up to 92 %) in vitro. Bio-(8)-MB-CPT thus exerted strong toxicity towards cervical cancer cells, but unlike the parent drug (camptothecin), showed no toxicity towards normal cells. Moreover, the prodrug displayed significantly enhanced antitumor efficacy in vivo and eradicated the tumor with no obvious side effects (inhibition of the tumor reached up to 99.9 %).
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http://dx.doi.org/10.1002/anie.202116807DOI Listing
March 2022

Platinum Iodide-Catalyzed Three-Component Cascade Cycloaddition Reactions between γ-Aminoalkynes and Electron-Deficient Alkynes.

J Org Chem 2021 Dec 9;86(23):16614-16624. Epub 2021 Nov 9.

The State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, P. R. China.

Herein, we report a protocol for PtI-catalyzed three-component cascade cycloaddition reactions between γ-aminoalkynes and electron-deficient alkynes to afford highly substituted cyclohexadiene--pyrrolidines in good yields. On the basis of the results of the control experiments and density functional theory calculations, we present a plausible mechanism that proceeds via two key intermediates. The overall transformation involves the cleavage and formation of multiple C-C and C-N bonds and a previously unreported reaction mode of a seven-membered nitrogen heterocyclic intermediate.
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http://dx.doi.org/10.1021/acs.joc.1c01913DOI Listing
December 2021

Traffic-related air pollution associated pulmonary pathophysiologic changes and cardiac injury in elderly patients with COPD.

J Hazard Mater 2022 02 9;424(Pt B):127463. Epub 2021 Oct 9.

Department of Occupational and Environmental Health, Peking University School of Public Health, and Peking University Institute of Environmental Medicine, Beijing, China; Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University, Beijing, China. Electronic address:

Traffic-related air pollution (TRAP) has shown enormous environmental toxicity, but its cardiorespiratory health impact on chronic obstructive pulmonary disease (COPD) has been less studied. We followed a panel of 45 COPD patients with 4 repeated clinical visits across 14 months in a traffic-predominated urban area of Beijing, China, with concurrent measurements of TRAP metrics (fine particulate matter, black carbon, oxides of nitrogen and carbon monoxide). Linear mixed-effect models were performed to evaluate the associations and potential pathways linking traffic pollution to indicators of spirometry, cardiac injury, inflammation and oxidative stress. We observed that interquartile range increases in moving averages of TRAP exposures at prior up to 7 days were associated with significant reductions in large and small airway functions, namely decreases in forced vital capacity of 3.1-9.3% and forced expiratory flow 25-75% of 5.9-16.4%. Higher TRAP levels were also associated with worsening of biomarkers relevant to lung injury (hepatocyte growth factor and surfactant protein D) and cardiac injury (high-sensitivity cardiac troponin I, B-type natriuretic peptide and soluble ST2), as well as enhanced airway/systemic inflammation and oxidative stress. Mediation analyses showed that TRAP exposures may prompt cardiac injury, possibly via worsening pulmonary pathophysiology. These findings highlight the importance of traffic pollution control priority in urban areas.
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http://dx.doi.org/10.1016/j.jhazmat.2021.127463DOI Listing
February 2022

Biological roles of l-carnitine in oocyte and early embryo development.

Mol Reprod Dev 2021 10 7;88(10):673-685. Epub 2021 Oct 7.

The New York Fertility Center, New York-Presbyterian Queens Affiliate with Weill Medical College of Cornell University, New York, New York, USA.

Poor oocyte quality is responsible for female infertility. Multiple studies have been carried out to find supplements to enhance oocyte quality and mitigate infertility problems. l-carnitine and its derivatives have diverse roles in developing oocytes and early embryos. This review focuses on the in vitro and in vivo studies that using l-carnitine alone or in combination with other supplements for oocyte quality enhancement. The key roles of l-carnitine in oocyte quality and embryo growth were summarized, and the underlying mechanism was also elucidated. l-carnitine helps in the lipid metabolism process by controlling the transfer of fatty acids to mitochondria for β-oxidation. l-carnitine modulates glucose metabolism and enhances respiratory chain enzyme activity. Furthermore, it acts as an antioxidant to prevent oxidative damage and inhibit apoptosis, a signal in response to oxidative stress. Results show the potential of l-carnitine as a potential agent in assisted reproductive technology to improve oocyte quality and the subsequent embryonic development.
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http://dx.doi.org/10.1002/mrd.23542DOI Listing
October 2021

De novo design of self-assembly hydrogels based on Fmoc-diphenylalanine providing drug release.

J Mater Chem B 2021 10 27;9(41):8686-8693. Epub 2021 Oct 27.

Department of Chemistry, Fudan University, Shanghai 200438, P. R. China.

Short peptides with self-assembled nanostructures are widely applied in the areas of drug delivery systems and biomaterials. In this article, we create a new peptide-based hydrogelator (Fmoc-FFRRVR) based on -fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) through an approach to improve its hydrophilicity. Compared to Fmoc-FF, Fmoc-FFRRVR prefers to form a hydrogel under mild conditions, and the gelation time is only 2 s. Fmoc-FFRRVR self-assembles into organized arrays of β-sheets in nanofibers π-stacking of Fmoc-FF, which are supported by circular dichroism and fluorescence emission spectroscopy. Rheology results confirm that the hydrogel of Fmoc-FFRRVR is elastic, reversible and injectable. The newly discovered hydrogel not only retains some excellent performances of Fmoc-FF, but also can be used as a drug carrier for biomedical applications.
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http://dx.doi.org/10.1039/d1tb01628hDOI Listing
October 2021

Phosphate adsorption characteristics of La(OH)-modified, canna-derived biochar.

Chemosphere 2022 Jan 4;286(Pt 2):131773. Epub 2021 Aug 4.

School of Ecology and Environmental Science YNU, Yunnan University, Kunming, 650091, China. Electronic address:

La(OH)-modified canna biochar (CBC-La) was prepared by a coprecipitation method (dipping method), and its phosphate adsorption characteristics were investigated. The results show that the pseudo-second-order kinetics and the Langmuir model can be used to describe the adsorption process with a high level of accuracy. Adsorption equilibrium could be reached at 8 h, at which point the maximum adsorption capacity was shown to be 37.37 mg/g. CBC-La has excellent phosphate adsorption capacity in the middle to low concentrations (≤50 mg/L), and its removal rate can exceed 99 %. CBC-La also has wide pH adaptability (3-9) and a strongly selective adsorption performance. Notably, it can still maintain a removal rate of over 99.8 % in the presence of certain anions (NO, HCO, and CO), and the presence of NH has a synergistic effect on the adsorption process. Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) measurements demonstrate that the main mechanisms of CBC-La phosphate adsorption are electrostatic adsorption, ion exchange, ligand exchange and inner sphere complexation.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131773DOI Listing
January 2022

A review on reducing indoor particulate matter concentrations from personal-level air filtration intervention under real-world exposure situations.

Indoor Air 2021 11 10;31(6):1707-1721. Epub 2021 Aug 10.

Department of Occupational and Environmental Health, Peking University School of Public Health, and Peking University Institute of Environmental Medicine, Beijing, China.

Improving air quality in indoor environments where people live is of importance to protect human health. In this systematic review, we assessed the effectiveness of personal-level use of air filtration units in reducing indoor particulate matters (PM) concentrations under real-world situations following systematic review guidelines. A total of 54 articles were included in the review, in which 20 randomized controlled/crossover trials that reported the changes in indoor fine PM (PM ) concentrations were quantitatively assessed in meta-analysis. Standardized mean differences (SMDs) were calculated for changes in indoor PM concentrations following air filtration interventions. Moderate-to-large reductions of 11%-82% in indoor PM  concentrations were observed with SMD of -1.19 (95% CI: -1.50, -0.88). The reductions in indoor PM concentrations varied by geographical locations, filtration technology employed, indoor environmental characteristics, and air pollution sources. Most studies were graded with low-to-moderate risk of bias; however, the overall certainty of evidence for indoor PM concentration reductions was graded at very low level. Considering the effectiveness of indoor air filtration under practical uses, socio-economic disparities across study populations, and costs of air filter replacement over time, our results highlight the importance of reducing air pollution exposure at the sources.
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http://dx.doi.org/10.1111/ina.12922DOI Listing
November 2021

Blocking MCT4 SUMOylation inhibits the growth of breast cancer cells.

Mol Carcinog 2021 10 4;60(10):702-714. Epub 2021 Aug 4.

Department of Immunology, School of Medicine, Nankai University, Tianjin, China.

Monocarboxylate transporter 4 (MCT4) is highly expressed in various types of solid neoplasms including breast cancer (BC); however, the pro-tumor functions underlying its increased expression have not been explained. Here, we examined the roles of posttranslational modifications to MCT4 in BC, particularly SUMOylation. Our findings revealed that SUMOylation of MCT4 inhibited its degradation and stabilized MCT4 protein levels, while ubiquitination facilitated MCT4 degradation. The E3 ubiquitin ligases β-TRCP and FBW7 interacted with MCT4 at the DSG-box and TPETS sequences, respectively, and Lys448 (K448) of MCT4 could be modified by SUMO chains. Our key finding was that K448 was crucial for MCT4 SUMOylation. Moreover, mutations of K448 abolished MCT4 expression, delaying the growth of BC. This study suggested that SUMOylation of K448 increased MCT4 levels, and mutations of K448 in MCT4 could have therapeutic significance in BC.
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http://dx.doi.org/10.1002/mc.23336DOI Listing
October 2021

HOCl-Activated Aggregation of Gold Nanoparticles for Multimodality Therapy of Tumors.

Adv Sci (Weinh) 2021 09 8;8(17):e2100074. Epub 2021 Jul 8.

Department of Chemistry, Fudan University, Shanghai, 200438, China.

Tumor microenvironment-responsive nanodrugs offer promising opportunities for imaging-guided precision therapy with reduced side effects. Considering that the antitumor effect is closely related to the size of the nanodrugs, it is particularly important to develop a therapeutic system with size adjustability in the tumor microenvironment, which is still a great challenge in the field of nanotheranostics. Herein, a reactive oxygen species (ROS)-activated aggregation strategy is reported for imaging-guided precision therapy of tumors. The ROS-activated nanoplatform is constructed based on gold nanoparticles (AuNPs) coated with an HOCl probe on its surface (namely, Au-MB-PEG NPs). The Au-MB-PEG NPs show high sensitivity toward HOCl, resulting in the modulation of surface charge and rapid aggregation of AuNPs, and simultaneous release of methylene blue as a photosensitizer for photodynamic therapy (PDT). In the tumor environment, the aggregated AuNPs ensure higher tumor accumulation and retention. Furthermore, the redshift of the absorption of aggregated AuNPs leads to activated photoacoustic imaging signals and photothermal therapy (PTT) under near-infrared irradiation. Au-MB-PEG NPs thus efficiently inhibit the tumor growth through combined PTT-PDT therapy. This work contributes to the design of stimuli-induced size-aggregation nanodrugs, thereby attaining advanced performance in cancer diagnosis and treatment.
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http://dx.doi.org/10.1002/advs.202100074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425924PMC
September 2021

Follicular Metabolites-Assisted Clinical Evaluation of IVF/ICSI Outcomes.

Evid Based Complement Alternat Med 2021 26;2021:9999659. Epub 2021 May 26.

Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.

As infertility became a significant public health problem, assisted reproductive technologies (ARTs) were introduced. However, the fertilization rate of in vitro fertilization (IVF) per cycle varied, and patients needed to repeat IVF or change to intracytoplasmic sperm injection (ICSI). Here, 75 couples suffering from female fallopian tubal blockage (tubal group) and 42 spouses beset by male abnormal sperm status (dysspermia group) were recruited. We comprehensively explored the relationship among couples' clinical factors, follicular metabolites, and IVF/ICSI stepwise outcomes. IVF/ICSI outcomes were affected by follicular metabolites and physical status in both women and men, regardless of which side infertility came from. Particularly, in the tubal group, the energy supporting pathways-glycolysis and pyruvate metabolism-were most essential in follicles, and IVF/ICSI outcomes were also related to sperm parameters. However, in the dysspermia group, in addition to sperm conditions, oocyte quality acted as a compensation for poor sperm quality, for which aminoacyl-tRNA biosynthesis and the related supporting metabolism were critical in the follicular environment, and ultimately played a decisive role in IVF/ICSI outcomes. The respective logistic regression models in combination with selective male sperm parameters, estradiol (E2), follicular alanine, glutamine, glycoprotein, lipid, and acetic acid, were constructed to predict IVF or ICSI outcomes. No matter which sex infertility comes from, factors from both men and women should be considered. The current study provides a feasible option for pre-IVF evaluation, as well as guidance for follow-up clinical intervention to improve IVF/ICSI success rates.
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http://dx.doi.org/10.1155/2021/9999659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189786PMC
May 2021

Combustion-derived particulate organic matter associated with hemodynamic abnormality and metabolic dysfunction in healthy adults.

J Hazard Mater 2021 09 29;418:126261. Epub 2021 May 29.

Department of Occupational and Environmental Health Sciences, Peking University School of Public Health, and Peking University Institute of Environmental Medicine, Beijing, China; Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Health Science Center, Peking University, Beijing, China. Electronic address:

Epidemiological evidence on cardiometabolic health of particulate organic matter (POM) and its sources is sparse. In a panel of 73 healthy adults in Beijing, China, daily concentrations of ambient fine particulate matter-bound polycyclic aromatic hydrocarbons (PAHs) and n-alkanes were measured throughout the study period, and Positive Matrix Factorization approach was used to identity PAHs sources. Linear mixed-effect models and mediation analyses were applied to examine the associations and potential interlink pathways between POM and biomarkers indicative of hemodynamics, insulin resistance, vascular calcification and immune inflammation. We found that significant alterations in cardiometabolic measures were associated with POM exposures. In specific, interquartile range increases in PAHs concentrations at prior up to 9 days were observed in association with significant elevations of 2.6-2.9% in diastolic blood pressure, 6.6-8.1% in soluble ST2, 10.5-14.5% in insulin, 40.9-45.7% in osteoprotegerin, and 36.3-48.7% in interleukin-17A. Greater associations were generally observed for PAHs originating from traffic emissions and coal burning. Mediation analyses revealed that POM exposures may prompt the genesis of hemodynamic abnormalities, possibly via worsening insulin resistance and calcification potential. These findings suggested that cardiometabolic health benefits would be achieved by reducing PM from combustion emissions.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126261DOI Listing
September 2021

Au(I)/()-BINOL-Ti(IV) Concerted Catalyzed Asymmetric Cascade Cycloaddition Reaction of Arylalkynols.

Org Lett 2021 May 22;23(9):3573-3577. Epub 2021 Apr 22.

State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, P. R. China.

An efficient catalytic asymmetric cascade cycloaddition reaction of arylalkynols with dioxopyrrolidines was developed. This reaction was achieved using Au(I) and ()-BINOL-Ti(IV) bimetallic catalysts and exclusively delivered a series of chiral oxo-bridged bicyclic benzooxacine compounds in up to 86% yield with 96% as well as >33:1 . Meanwhile, three new σ bonds and three new stereogenic centers were formed in a one-pot process.
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http://dx.doi.org/10.1021/acs.orglett.1c00976DOI Listing
May 2021

Inhibitory Activity of Pyrroloisoxazolidine Derivatives against .

Biomed Res Int 2021 13;2021:8889247. Epub 2021 Mar 13.

School of Pharmacy, Nantong University, Nantong 226001, China.

The obligate intracellular bacterium is a group of worldwide human pathogens that can lead to serious reproductive problems. The frequent clinical treatment failure promoted the development of novel antichlamydial agents. Here, we firstly reported a group of pyrroloisoxazolidine-inhibited in a dose-dependent manner . Among them, compounds 1 and 2 exhibited the strongest inhibitory activity with IC values from 7.25 to 9.73 M. The compounds disturbed the whole intracellular life cycle of , mainly targeting the middle reticulate body proliferation stages. Besides, the compounds partially inhibited the chlamydial infection by reducing elementary body infectivity at high concentration. Our findings suggest the potential of pyrroloisoxazolidine derivatives as promising lead molecules for the development of antichlamydial agents.
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http://dx.doi.org/10.1155/2021/8889247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984888PMC
May 2021

Enhanced anticancer effect of doxorubicin by TPGS-coated liposomes with Bcl-2 siRNA-corona for dual suppression of drug resistance.

Asian J Pharm Sci 2020 Sep 12;15(5):646-660. Epub 2019 Nov 12.

College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.

Multiple drug resistance (MDR) is a tough problem in developing hepatocellular carcinoma (HCC) therapy. Here, we developed TPGS-coated cationic liposomes with Bcl-2 siRNA corona to load doxorubicin (Dox) , Bcl-2 siRNA/Dox-TPGS-LPs, to enhance anticancer effect of Dox in HCC-MDR. TPGS , d-α-tocopheryl polyethylene glycol 1000 succinate, inhibited P-glycoprotein (P-gp) efflux pump and Bcl-2 siRNA suppressed anti-apoptotic Bcl-2 protein. The Bcl-2 siRNA loaded in the liposomal corona was observed under transmission electron microscopy. The stability and hemolysis evaluation demonstrated Bcl-2 siRNA/Dox-TPGS-LPs had good biocompatibility and siRNA-corona could protect the liposomal core to avoid the attachment of fetal bovine serum. In drug-resistant cells, TPGS effectively prolonged intracellular Dox retention time and siRNA-corona did improve the internalization of Dox from liposomes. and anticancer effect of this dual-functional nanostructure was examined in HCC-MDR Bel7402/5-FU tumor model. MTT assay confirmed the IC value of Dox was 20-50 fold higher in Bel7402/5-FU MDR cells than that in sensitive Bel7402 cells. Bcl-2 siRNA corona successfully entered the cytosol of Bel7402/5-FU MDR cells to downregulate Bcl-2 protein levels and . Bcl-2 siRNA/Dox-TPGS-LPs showed superior to TPGS- (or siRNA-) linked Dox liposomes in cell apoptosis and cytotoxicity assay in Bel7402/5-FU MDR cells, and 7-fold greater effect than free Dox in tumor growth inhibition of Bel7402/5-FU xenograft nude mice. In conclusion, TPGS-coated cationic liposomes with Bcl-2 siRNA corona had the capacity to inhibit MDR dual-pathways and subsequently improved the anti-tumor activity of the chemotherapeutic agent co-delivered to a level that cannot be achieved by inhibiting a MDR single way.
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http://dx.doi.org/10.1016/j.ajps.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610212PMC
September 2020

Comprehensive Analysis of mRNA and lncRNA Transcriptomes Reveals the Differentially Hypoxic Response of Preadipocytes During Adipogenesis.

Front Genet 2020 6;11:845. Epub 2020 Aug 6.

Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.

Local hypoxia has recently been reported to occur in the white adipose tissue (WAT) microenvironment during obesity. Adipocytes have a unique life cycle that reflects the different stages of adipogenesis in the WAT niche. Long non-coding RNAs (lncRNAs) play an important role in the cellular response to hypoxia. However, the differentially hypoxic responses of preadipocytes during adipogenesis and the potential role of lncRNAs in this process remain to be elucidated. Here, we evaluated the differentially hypoxic responses of primary hamster preadipocytes during adipogenesis and analyzed mRNA and lncRNA expression in same Ribo-Zero RNA-seq libraries. Hypoxia induced HIF-1α protein during adipogenesis and caused divergent changes of cell phenotypes. A total of 10,318 mRNAs were identified to be expressed in twenty libraries (five timepoints), and 3,198 differentially expressed mRNAs (DE mRNAs) were detected at five timepoints (hypoxia vs. normoxia). Functional enrichment analysis revealed the shared and specific hypoxia response pathways in the different stages of adipogenesis. Hypoxia differentially modulated the expression profile of adipose-associated genes, including adipokines, lipogenesis, lipolysis, hyperplasia, hypertrophy, inflammatory, and extracellular matrix. We also identified 4,296 lncRNAs that were expressed substantially and detected 1,431 DE lncRNAs at five timepoints. Two, 3, 5, 13, and 50 DE mRNAs at D0, D1, D3, D7, and D11, respectively, were highly correlated and locus-nearby DE lncRNAs and mainly involved in the cell cycle, vesicle-mediated transport, and mitochondrion organization. We identified 28 one-to-one lncRNA-mRNA pairs that might be closely related to adipocyte functions, such as -, -, and -. These lncRNAs may represent the crucial regulation axis in the cellular response to hypoxia during adipogenesis. This study dissected the effects of hypoxia in the cell during adipogenesis, uncovered novel regulators potentially associated with WAT function, and may provide a new viewpoint for interpretation and treatment of obesity.
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http://dx.doi.org/10.3389/fgene.2020.00845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425071PMC
August 2020

Comparative microRNA Transcriptomes in Domestic Goats Reveal Acclimatization to High Altitude.

Front Genet 2020 31;11:809. Epub 2020 Jul 31.

Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China.

High-altitude acclimatization is a representative example of vertebrates' acclimatization to harsh and extreme environments. Previous studies reported sufficient evidence for a molecular genetic basis of high-altitude acclimatization, and genomic patterns of genetic variation among populations and species have been widely elucidated in recent years. However, understanding of the miRNA role in high-altitude acclimatization have lagged behind, especially in non-model species. To investigate miRNA expression alterations of goats that were induced by high-altitude stress, we performed comparative miRNA transcriptome analysis on six hypoxia-sensitive tissues (heart, kidney, liver, lung, skeletal muscle, and spleen) in two goat populations from distinct altitudes (600 and 3000 m). We obtained the expression value of 1391 mature miRNAs and identified 138 differentially expressed (DE) miRNAs between high and low altitudes. Combined with tissue specificity analysis, we illustrated alterations of expression levels among altitudes and tissues, and found that there were coexisting tissue-specific and -conserved mechanisms for hypoxia acclimatization. Notably, the interplay between DE miRNA and DE target genes strongly indicated post-transcriptional regulation in the hypoxia inducible factor 1, insulin, and p53 signaling pathways, which might play significant roles in high-altitude acclimatization in domestic goats. It's also worth noting that we experimentally confirmed miR-106a-5p to have a negative regulation effect on angiogenesis by directly targeting . These results provide insight into the complicated miRNA expression patterns and regulatory mechanisms of high-altitude acclimatization in domestic goats.
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http://dx.doi.org/10.3389/fgene.2020.00809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411263PMC
July 2020

Multifunctional Smart Yolk-Shell Nanostructure with Mesoporous MnO Shell for Enhanced Cancer Therapy.

ACS Appl Mater Interfaces 2020 Sep 20;12(35):38906-38917. Epub 2020 Aug 20.

Department of Chemistry, Fudan University, Shanghai 200438, P. R. China.

Manganese dioxide (MnO) nanostructures have aroused great interest among analytical and biological medicine researchers as a unique type of tumor microenvironment (TME)-responsive nanomaterial. However, reliable approaches for synthesizing yolk-shell nanostructures (YSNs) with mesoporous MnO shell still remain exciting challenges. Herein, a YSN (size, ∼75 nm) containing a mesoporous MnO shell and Er-doped upconversion/downconversion nanoparticle (UCNP) core with a large cavity is demonstrated for the first time. This nanostructure not only integrates diverse functional components including MnO, UCNPs, and YSNs into one system but also endows a size-controllable hollow cavity and thickness-tunable MnO layers, which can load various guest molecules like photosensitizers, methylene blue (MB), and the anticancer drugs doxorubicin (DOX). NIR-II fluorescence and photoacoustic (PA) imaging from UCNP and MB, respectively, can monitor the enrichment of the nanomaterials in the tumors for guiding chemo-photodynamic therapy (PDT) . In the TME, degradation of the mMnO shell by HO and GSH not only generates Mn for tumor-specific T-MR imaging but also releases O and drugs for tumor-specific treatment. The result confirmed that imaging-guided enhanced chemo-PDT combination therapy that benefited from the unique structural features of YSNs could substantially improve the therapeutic effectiveness toward malignant tumors compared to monotherapy.
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http://dx.doi.org/10.1021/acsami.0c08389DOI Listing
September 2020

pH-responsive AgS nanodots loaded with heat shock protein 70 inhibitor for photoacoustic imaging-guided photothermal cancer therapy.

Acta Biomater 2020 10 13;115:358-370. Epub 2020 Aug 13.

Department of Chemistry and Collaborative Innovation Center of Chemistry for Energy Materials, Fudan University, 2005 Songhu Road, Shanghai 200438, China; State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China. Electronic address:

Heat-treated cancer cells have thermo-resistance due to the up-regulated levels of heat shock proteins (HSP) resulting in low therapeutic efficiency and ineffective ablation of tumors. In this work, we report pH-responsive AgS nanodots (AgS NDs) loaded with HSP70 inhibitor (QE-PEG-AgS) for enhanced photothermal cancer therapy. QE-PEG-AgS was easily prepared via self-assembly of hydrophobic AgS NDs, amphiphilic pH-responsive PEG-PAE polymer, and an HSP70 inhibitor quercetin (QE). QE-PEG-AgS has ideal water-solubility and biocompatibility, can rapidly enter cells, and preferentially accumulate in cell lysosomes. The slightly acidic environment of tumor cells and the acidity of lysosomes as well as the high temperature generated by photothermal therapy under irradiation of NIR light (808 nm) promote the release of the inhibitor molecules to reduce the heat resistance of cancer cells and improve the in vivo photothermal therapy efficiency. Moreover, QE-PEG-AgS has good photoacoustic imaging (PAI) ability; this QE-PEG-AgS concentration dependent signal can precisely follow the accumulation of the nanomaterials in tumors and dictate the correct time for light therapy. As a result, QE-PEG-AgS achieved complete tumor ablation effect with no recurrence when only irradiated with NIR light for 10 min. This approach offers a new approach for the theranostic applications of AgS NDs. STATEMENT OF SIGNIFICANCE: In this work, pH-responsive AgS nanodots loaded with the heat shock protein inhibitor for enhanced photothermal cancer therapy have been simply prepared via self-assembly process. This nanoagent possesses ideal water-solubility and biocompatibility, can rapidly enter cells, and preferentially accumulate in cell lysosomes. The acidic environment of tumor cells and the acidity of lysosomes, as well as the high temperature generated by photothermal therapy under irradiation of NIR light promote the release of the inhibitor molecules from the nanoagent to improve the in vivo photothermal therapy efficiency. Moreover, the photoacoustic imaging (PAI) of the nanoagent can precisely follow the accumulation of the nanomaterials in tumors and dictate the light therapy time to guarantee the complete tumor ablation effect with no recurrence.
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http://dx.doi.org/10.1016/j.actbio.2020.08.007DOI Listing
October 2020

The critical size of gold nanoparticles for overcoming P-gp mediated multidrug resistance.

Nanoscale 2020 Aug 17;12(31):16451-16461. Epub 2020 Jun 17.

School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.

Multidrug resistance (MDR) remains a huge obstacle during cancer treatment. One of the most studied MDR mechanisms is P-glycoprotein (P-gp) mediated drug efflux. Based on the three-dimensional structural characteristics of P-gp, gold nanoparticles (AuNPs) with average sizes of 4.1 nm and 5.4 nm were designed for the construction of nanodrug delivery systems (NanoDDSs), with the anticancer molecules 2-(9-anthracenylmethylene)-hydrazinecarbothioamide (ANS) and 6-mercaptopurine (6-MP) modified on the AuNP surfaces through the thiol group. In vitro cytotoxicity results suggested that the larger sized AuNPs can effectively decrease the drug resistance index of MCF-7/ADR cells to ∼2. Verapamil and P-gp antibody competitive experiments, combined with the cellular uptake of AuNPs, indicated that larger NanoDDSs were more conducive to intracellular drug accumulation and thus had improved anticancer activities, due to a size mismatch between the nanoparticles and the active site of P-gp, and, therefore, reduced drug efflux was seen. Measurements of ATPase activity and intracellular ATP levels indicated that the larger nanoparticles do not bind well to P-gp, thus avoiding effective recognition by P-gp. This was further evidenced by the observation that 4.1 nm and 5.4 nm NanoDDS-treated MCF-7/ADR cells showed remarkable differences in energy-related metabolic pathways. Therefore, the critical size of AuNPs for overcoming MDR was identified to be between 4.1 nm and 5.4 nm. This provides a more accurate description of the composite dimension requirements for NanoDDSs that are designed to overcome MDR.
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http://dx.doi.org/10.1039/d0nr03226cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430045PMC
August 2020

Dual-Modality Detection of Early-Stage Drug-Induced Acute Kidney Injury by an Activatable Probe.

ACS Sens 2020 08 7;5(8):2457-2466. Epub 2020 Aug 7.

Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200438, China.

Early detection of drug-induced acute kidney injury (AKI) is crucial for effective treatment and prevention of further injury. It remains challenging, however, because of the lack of activatable indicators with multimodality imaging capability that could increase the accuracy of diagnosis by mutual verification. Herein, we report an activatable probe, , that enabled dual-modality detection of the early-stage drug-induced AKI. was completely soluble in water and highly sensitive to hypochlorous acid (HOCl). Dramatic increases of both near-infrared (NIR) emission and absorption were observed after reaction with HOCl. A correlation between HOCl concentration and drug-induced AKI was established using as a tool. As a consequence, the HOCl-activated probe was able to detect the early-stage drug-induced AKI by dual-modality imaging, irrespective of the drug stimulation time or dosage, by combining NIR fluorescence and photoacoustic imaging.
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http://dx.doi.org/10.1021/acssensors.0c00640DOI Listing
August 2020

Detecting Basal Myeloperoxidase Activity in Living Systems with a Near-Infrared Emissive "Turn-On" Probe.

Anal Chem 2020 08 31;92(16):10971-10978. Epub 2020 Jul 31.

Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200433, China.

Detecting myeloperoxidase (MPO) activity in living organisms is important because MPO contributes to the pathogenesis of many diseases such as rheumatoid arthritis and other inflammatory diseases, artherosclerosis, neurodegenerative disease, and some cancers. However, rapid and effective methods for the detection of basal MPO activity in living systems have not yet been reported. Herein, we report a near-infrared (NIR) emissive "turn-on" probe that can specifically bind to MPO and accurately measure MPO activity in living cells and in vivo via a rapid response to initial hypochlorous acid (HOCl), produced by MPO. Notably, could detect the basal level of MPO activity in human promyelocytic leukemia cells (HL-60) and could discriminate between MPO high-expression and low-expression cells. Furthermore, was successfully applied to in vivo imaging of MPO in MPO-dependent diseases, such as arthritis and inflammatory bowel disease.
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http://dx.doi.org/10.1021/acs.analchem.9b04601DOI Listing
August 2020

Oestrogen induces epithelial-mesenchymal transition in endometriosis via circ_0004712/miR-148a-3p sponge function.

J Cell Mol Med 2020 09 15;24(17):9658-9666. Epub 2020 Jul 15.

Department of Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.

Endometriosis is a common, chronic gynaecologic disease affecting up to 10% of women in their reproductive age and leading to pain and infertility. Oestrogen (E )-induced epithelial-mesenchymal transition (EMT) process has been considered as a key factor of endometriosis development. Recently, the dysregulated circular RNAs (circRNAs) have been discovered in endometriosis tissues. However, the molecular mechanism of circRNAs on the E -induced EMT process in endometriosis is still unknown. Here, we demonstrated that circ_0004712 up-regulated by E treatment in endometrial epithelial cells. Knock-down the expression of circ_0004712 significantly suppressed E -induced cell migration activity. Meanwhile, we identified miR-148a-3p as a potential target miRNA of circ_0004712. Inhibited the expression of miR-148a-3p could recovered the effect of circ_0004712 knock-down in E -treated endometrial epithelial. Furthermore, Western blot assay showed that E treatment could increase the expression and activity of β-catenin, snail and N-cadherin and reduce the expression of E-cadherin. The expression and activity of β-catenin pathway were recovered by circ_0004712 knock-down or miR-148a-3p overexpression. Altogether, the results demonstrate that circ_0004712/miR-148a-3p plays an important role in E -induced EMT process in the development of endometriosis, and the molecular mechanism may be associated with the β-catenin pathway. This work highlighted the importance of circRNAs in the development of endometriosis and provide a new biomarker for diagnosis and therapies.
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http://dx.doi.org/10.1111/jcmm.15495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520264PMC
September 2020

A NIR fluorescent probe based on phenazine with a large Stokes shift for the detection and imaging of endogenous HO in RAW 264.7 cells.

Analyst 2020 Jun 5;145(12):4196-4203. Epub 2020 Jun 5.

Key Laboratory for Advanced Materials, Joint International Research Laboratory for Precision Chemistry and Molecular Engineering, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, PR China.

Hydrogen peroxide (HO), one of the reactive oxygen species (ROS), plays vital roles in diverse physiological processes. Thus, herein, to improve the signal-to-noise ratio, a new near-infrared region (NIR) fluorophore (PCN) based on reduced phenazine was developed. PCN was further designed as a "turn on" fluorescent probe (PCN-BP) for the detection of HO by introducing p-boratebenzyl. After HO was added, the p-boratebenzyl group in PCN-BP was oxidized to p-hydroxy benzyl; it then self-departed, forming PCN, which displayed 24-fold NIR emission at 680 nm with a large Stokes shift (more than 200 nm). This probe presented an excellent linear relation with the concentration of HO and good selectivity to various ions, ROS and biothiols; thus, it can be utilized as a colorimetric and fluorescence turn-on probe. More importantly, the probe was also employed for the exogenous and endogenous imaging of HO in RAW 264.7 cells.
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http://dx.doi.org/10.1039/d0an00153hDOI Listing
June 2020

Stereospecific Synthesis of -2,5-Disubstituted Pyrrolidines via ,-Acetals Formed by Hydroamination Cyclization-Hydroalkoxylation of Homopropargylic Sulfonamides in HFIP.

J Org Chem 2020 06 27;85(11):7045-7059. Epub 2020 May 27.

The State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, P. R. China.

We reported a novel two-step stereoselective synthesis of functionalized pyrrolidines from homopropargylic sulfonamides and nucleophiles via an isolable ,-acetal intermediates. This reaction features mild conditions and good scope of substrates. In addition, the use of hexafluoroisopropanol, acting as a solvent, an additive, a weak nucleophile, and a good leaving group, is pivotal to the success of the method. Moreover, reactions of chiral homopropargylic sulfonamides afford only 2,5--disubstituted pyrrolidines with high diastereoselectivity (up to >99:1 dr) and enantioselectivity (up to >99% ee). The overall reaction constitutes a formal 1,1-bifunctionalization of terminal alkynes, which has hitherto been reported only rarely. Additionally, this method provides efficient access to pharmaceutical intermediate and to carry out postmodification of natural products.
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http://dx.doi.org/10.1021/acs.joc.0c00403DOI Listing
June 2020

Anti-MRSA Activity of Actinomycin X and Collismycin A Produced by WA5-2-37 From the Intestinal Tract of American Cockroach ().

Front Microbiol 2020 7;11:555. Epub 2020 Apr 7.

School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China.

Methicillin-resistant (MRSA) is recognized as one of the serious pathogen that causes acquired infections worldwide. Its emerging need to discover novel, safe and potent anti-MRSA drugs. In this study, primary screening by anti-MRSA activity assay found one strain WA5-2-37 isolated from the intestinal tract of , exhibited great activity against MRSA ATCC 43300. The strain WA5-2-37 produced actinomycin X and collismycin A which showed strong inhibition of MRSA with minimum inhibitory concentration (MIC) values of 0.25 and 8 μg/mL. The structures of the pure compounds were elucidated by analysis of mass spectrometry (MS), H and C nuclear magnetic resonance (NMR). The strain WA5-2-37 was considered as on the basis of morphological characteristics, genotypic data, and phylogenetic analysis. This is the first reported naturally occurring strain of isolated from the intestinal tract of , whereas it has almost been found from plants, marine, and soil previously. Moreover, has not been reported to produce any anti-MRSA substances previously, such as actinomycin X and collismycin A. In conclusion, the insect-derived strain of WA5-2-37 was considered of great potential as a new strain of producing actinomycin X, collismycin A or other anti-MRSA compounds.
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http://dx.doi.org/10.3389/fmicb.2020.00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154055PMC
April 2020

Loss of hsa_circ_0118530 inhibits human granulosa-like tumor cell line KGN cell injury by sponging miR-136.

Gene 2020 Jun 24;744:144591. Epub 2020 Mar 24.

Department of Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, PR China. Electronic address:

Polycystic ovary syndrome (PCOS) is a kind of endocrine disease among women across the global. Recently, many researches have reported circular RNAs can act as significant molecular biomarkers for diseases, especially in tumors. Several Circular RNAs are reported to be aberrantly expressed in PCOS patients. Here, we investigated the biological effects of hsa_circ_0118530 on human granulosa cells, KGN. We observed that hsa_circ_0118530 was greatly elevated in PCOS patients and granulosa cells (including KGN and COV434 cells) compared to normal IOSE80 cells. hsa_circ_0118530 siRNA was transfected into KGN cells. We found that KGN cell viability was repressed, cell apoptosis was induced while cell migration was greatly inhibited. TGF-β1 was utilized to induce EMT process. As shown, loss of hsa_circ_0118530 significantly enhanced E-cadherin mRNA and protein levels while depressed N-cadherin expression. Furthermore, we indicated that decrease of hsa_circ_0118530 was able to inhibit ROS accumulation, MDA levels while induced SOD activity. Next, it was demonstrated that releases of inflammatory cytokine were suppressed by hsa_circ_0118530 down-regulation. Additionally, miR-136 was predicted and confirmed as the target of hsa_circ_0118530. For another, the functions of hsa_circ_0118530 on KGN cell progression, oxidative stress and inflammation releases were obviously reversed by miR-136 suppression. In conclusion, knockdown of hsa_circ_0118530 repressed PCOS progression via sponging miR-136.
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http://dx.doi.org/10.1016/j.gene.2020.144591DOI Listing
June 2020
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