Publications by authors named "Xia Yuan"

169 Publications

circASS1 overexpression inhibits the proliferation, invasion and migration of colorectal cancer cells by regulating the miR-1269a/VASH1 axis.

Exp Ther Med 2021 Oct 10;22(4):1155. Epub 2021 Aug 10.

Department of Medical Oncology, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, Guangdong 516000, P.R. China.

Colorectal cancer (CRC), the third most common cancer worldwide, poses a threat to human life. However, its underlying mechanism is unclear and no satisfactory treatment is available. The present study aimed to investigate the role of circular RNA argininosuccinate synthase 1 (circASS1) in CRC cells and tissues to identify the potential mechanism underlying the pathogenesis of CRC. The expression of circASS1 in CRC cells and tissues was determined by reverse transcription-quantitative PCR. Following circASS1 overexpression in HT29 cells, cell viability, colony formation and apoptosis were measured using MTT, colony formation and TUNEL assays, respectively. Cell invasion and migration were also assessed. After confirming the associations among circASS1, microRNA (miR)-1269a and vasohibin 1 (VASH1), the characteristics of the HT29 cell line were assessed by performing the aforementioned assays. circASS1 expression was decreased in CRC cells and tissues, and circASS1 overexpression suppressed CRC cell proliferation, invasion and migration. circASS1 adsorbed miR-1269a and regulated its expression, and VASH1 was a target protein of miR-1269a. circASS1 overexpression decreased cell proliferation, invasion and migration, but enhanced cell apoptosis in HT29 cells, which was reversed by co-transfection with miR-1269a mimic or short hairpin RNA-VASH1. In conclusion, circASS1 overexpression inhibited CRC cell proliferation, invasion and migration by regulating miR-1269a/VASH1, which indicated a potential molecular mechanism underlying the pathogenesis of CRC.
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http://dx.doi.org/10.3892/etm.2021.10589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393656PMC
October 2021

M6A methylation of DEGS2, a key ceramide-synthesizing enzyme, is involved in colorectal cancer progression through ceramide synthesis.

Oncogene 2021 Aug 6. Epub 2021 Aug 6.

Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

N6-methyladenosine (m6A) is the most prevalent RNA epigenetic regulator in cancer. However, the understanding of m6A modification on lipid metabolism regulation in colorectal cancer (CRC) is very limited. Here, we observed that human CRCs exhibited increased m6A mRNA methylation mediated by dysregulation of m6A erasers and readers. By performing methylated RNA-immunoprecipitation sequencing (MeRIP-seq) and transcriptomic sequencing (RNA-seq), we identified DEGS2 as a downstream target of m6A dysregulation. Overexpression or knockdown of DEGS2 confirmed the role of DEGS2 in proliferation, invasion and metastasis of CRC both in vitro and in vivo. Mechanistic studies identified the specific m6A modification site within DEGS2 mRNA, and mutation of this target site was found to drastically enhance the proliferative and invasive ability of CRC cells in vitro and promote tumorigenicity in vivo. Lipidome analysis showed that lipid metabolism was dysregulated in CRC. Moreover, ceramide synthesis was suppressed due to DEGS2 upregulation mediated by m6A modification in CRC tissues. Our findings highlight that the function of DEGS2 m6A methylation in CRC and extend the understanding of the importance of RNA epigenetics in cancer biology.
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http://dx.doi.org/10.1038/s41388-021-01987-zDOI Listing
August 2021

Effects of water-soluble components of atmospheric particulates from rare earth mining areas in China on lung cancer cell cycle.

Part Fibre Toxicol 2021 08 2;18(1):27. Epub 2021 Aug 2.

School of Public Health, Inner Mongolia Autonomous Region, Jinshan Economic and Technological Development Zone, Inner Mongolia Medical University, Inner Mongolia Autonomous Region, 010010, Hohhot, China.

Background: This study aims to investigate the effects of water soluble particulate matter (WSPM) on the viability and protein expression profile of human lung adenocarcinoma cell A549 in the Bayou Obo rare earth mining area, and explore the influence of WSPM on the A549 cell cycle.

Results: It was found that WSPM can inhibit the viability of A549 cells and induce cell arrest in the G2/M phase. Compared with controls, exposure to WSPM10 and WSPM2.5 induced 134 and 116 proteins to be differentially expressed in A549 cells, respectively. In addition, 33 and 31 differentially expressed proteins were further confirmed, and was consistent with the proteomic analysis. The most prominent enrichment in ribosome-associated proteins were presented. When RPL6, RPL13, or RPL18A gene expression was inhibited, A549 cells were arrested in the G1 phase, affecting the expression of Cyclin D1, p21, RB1, Cyclin A2, Cyclin B1, CDC25A, CDK2, CHEK2 and EF. Furthermore, the La, Ce, Nd and F in WSPM also inhibited the viability of A549 cells. After 24 h of exposure to 2 mM of NaF, A549 cells were also arrested in the G2/M phase, while the other three compounds did not have this effect. These four compounds affected the cell cycle regulatory factors in A549 cells, mainly focusing on effecting the expression of CDK2, CDK4, RB1, ATM, TP53 and MDM2 genes. These results are consistent with the those from WSPM exposure.

Conclusions: These results revealed that WSPM from rare earth mines decreased the viability of A549 cells, and induced cell cycle G2/M phase arrest, and even apoptosis, which may be independent of the NF-κB/MYD88 pathway, and be perceived by the TLR4 receptor. The dysfunction of the cell cycle is correlated to the down-expression of ribosomal proteins (RPs). However, it is not the direct reason for the A549 cell arrest in the G2/M phase. La, Ce, and F are probably the main toxic substances in WSPM, and may be regulate the A549 cell cycle by affecting the expression of genes, such as MDM2, RB1, ATM, TP53, EF, CDK2 and CDK4. These results indicate the importance for further research into the relationship between APM and lung cancer.
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http://dx.doi.org/10.1186/s12989-021-00416-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330054PMC
August 2021

The Value of Cervical Node Features in Predicting Long-Term Survival of Nasopharyngeal Carcinoma in the Intensity-Modulated Radiotherapy Era.

Cancer Manag Res 2021 21;13:4899-4909. Epub 2021 Jun 21.

Department of Radiation Oncology, Sun Yat-Sen University Cancer Centre; State Key Laboratory of Oncology in South China; Collaborative Innovation Centre for Cancer Medicine, Guangdong, People's Republic of China.

Objective: To investigate the prognostic value of cervical node features in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT) and build a prognostic nomogram to predict the long-term survival.

Methods: In this study, 1752 patients after IMRT from 2008 to 2011 were recruited. The clinical and laboratory characteristics and the nodal features including the nodal number, maximum dimension diameter, extranodal extension (ENE), and cervical node necrosis (CNN) were retrospective analyzed. Univariate Cox and multivariate proportional hazard regression models were used to test the prognostic value of nodal features. Prognostic nomograms were established to predict survival.

Results: The 10-year distant metastases-free survival (DMFS) and disease-specific survival (DSS) rates were 86.5% and 80.8%, respectively. Multivariate analysis showed that age, sex, lactate dehydrogenase (LDH), CNN, ENE, T stage, and N stage were independent factors for DSS. Two nomograms-nomogram A (without nodal features) and nomogram B (with nodal features)-were built. The calibration curve for the probability of DSS showed good agreement between prediction by nomogram and the actual observation. The C-index of nomogram B was higher than that for nomogram A in predicting DSS (0.708 vs 0.676, P<0.01).

Conclusion: The nodal features including ENE and CNN were negative prognostic factors for NPC, and the prognostic nomogram incorporating the nodal features was more accurate in predicting survival than the nomogram without nodal features.
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http://dx.doi.org/10.2147/CMAR.S312161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233002PMC
June 2021

Bevacizumab biosimilar LY01008 compared with bevacizumab (Avastin) as first-line treatment for Chinese patients with unresectable, metastatic, or recurrent non-squamous non-small-cell lung cancer: A multicenter, randomized, double-blinded, phase III trial.

Cancer Commun (Lond) 2021 Sep 29;41(9):889-903. Epub 2021 Jun 29.

Respiratory Department, Taizhou Hospital of Zhejiang Province, Taizhou, Zhejiang, 317000, P. R. China.

Background: Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first-line treatment of Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC).

Methods: Stage IIIB-IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4-6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127).

Results: Between December 15 , 2017, and May 15 , 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25 , 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1-6) and median duration of treatment of 3.0 (range 0.0-5.1) months. ORR of response-evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80-1.04, within the prespecified equivalence margin of 0.75-1.33). Up to May 15 , 2020, with a median follow-up of 13.6 (range 0.8-28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1-year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups.

Conclusions: LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non-squamous NSCLC patients in the first-line setting.
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http://dx.doi.org/10.1002/cac2.12179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441057PMC
September 2021

Crystalline silica induces macrophage necrosis and causes subsequent acute pulmonary neutrophilic inflammation.

Cell Biol Toxicol 2021 Jun 25. Epub 2021 Jun 25.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.

Crystalline silica (CS), an airborne particulate, is a major global occupational health hazard. While it is known as an important pathogenic factor in many severe lung diseases, the underlying mechanisms of its toxicity are still unclear. In the present study, we found that intra-tracheal instillation of CS caused rapid emergence of necrotic alveolar macrophages. Cell necrosis was a consequence of the release of cathepsin B in CS-treated macrophages, which caused dysfunction of the mitochondrial membrane. Damage to mitochondria disrupted Na/K ATPase activity in macrophages, leading to intracellular sodium overload and the subsequent cell necrosis. Further studies indicate that CS-induced macrophage necrosis and the subsequent release of mitochondrial DNA could trigger the recruitment of neutrophils in the lung, which was regulated by the TLR9 signaling pathway. In conclusion, our results suggest a novel mechanism whereby CS leads to rapid macrophage necrosis through cathepsin B release, following the leakage of mitochondrial DNA as a key event in the induction of pulmonary neutrophilic inflammation. This study has important implications for the early prevention and treatment of diseases induced by CS.
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http://dx.doi.org/10.1007/s10565-021-09620-1DOI Listing
June 2021

Effect of continuity of care on anticoagulant therapy and quality of life after heart valve replacement: a systematic review and meta-analysis.

Ann Palliat Med 2021 May;10(5):5568-5579

Department of Nursing, Zhongshan Hospital, Fudan University, Shanghai, China.

Background: Valvular heart disease (VHD) is a leading cause of heart diseases and death, and heart valve replacement (HVR) plays a fundamental role in treating valve disease and improving the function of valves. The lack of continuity of care (CC, also known as transitional care) for postoperative patients after discharge often results in a variety of complications, bringing severe pain to the patients and diminishing their quality of life.

Methods: We systematically searched for relevant randomized controlled trials (RCTs) in Cochrane databases, PubMed, Embase, CINAHL, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Chongqing VIP, and Wanfang Data. The methodological quality of the included articles was assessed using the Cochrane Handbook for Systematic Reviews of Interventions. The meta-analysis was conducted with RevMan 5.2 software.

Results: A total of 14 RCTs (involving 1,825 patients), all in Chinese language, were included in the analysis, including 920 patients in the CC group and 905 patients in the control group (receiving the routine care). Meta-analysis showed that, compared with the control group, the CC group had significantly higher anticoagulation therapy adherence [RR =1.36, 95% CI: (1.25,1.48), P<0.00001], higher awareness of anticoagulation [RR =1.14, 95% CI: (1.09, 1.18), P<0.0001], and lower incidences of anticoagulation complications and adverse events [RR =0.24, 95% CI: (0.17, 0.35), P<0.00001]. In addition, the 5 domains reflecting quality of life including physical domain [MD =2.38, 95% CI: (1.30, 3.46), P<0.0001], psychological domain [MD =2.92, 95% CI: (1.47, 4.37), P<0.0001], levels of independence [MD =4.03, 95% CI: (1.04, 7.01), P=0.008], social relationships [MD=2.56, 95% CI: (1.81, 3.32), P<0.00001], and environment [MD =4.15, 95% CI: (1.16,7.14), P=0.007] were also significantly improved.

Discussion: Our results showed CC can effectively improve patients' anticoagulation therapy adherence and raise their awareness about medications, reduce the incidences of complications and adverse events, and thus improve the patients' quality of life. However, only a limited number of high-quality RCTs were included in our current analysis, and studies with more rigorous designs are warranted to further validate the impacts of CC on anticoagulation therapy adherence and quality of life after HVR.
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http://dx.doi.org/10.21037/apm-21-1167DOI Listing
May 2021

Plant and microbial regulations of soil carbon dynamics under warming in two alpine swamp meadow ecosystems on the Tibetan Plateau.

Sci Total Environ 2021 Oct 27;790:148072. Epub 2021 May 27.

Institute of Ecology, College of Urban and Environmental Sciences, Key Laboratory for Earth Surface Processes of the Ministry of Education, Peking University, Beijing 100871, China. Electronic address:

Increasing temperature plays important roles in affecting plant and soil microbial communities as well as ecological processes and functions in terrestrial ecosystems. However, mechanisms of warming influencing soil carbon dynamics associated with plant-microbe interactions remain unclear. In this study, open-top chambers (OTCs) experiments were carried out to detect the responses of plants, soil microbes, and SOC contents, physical fractions (by particle-size fractionation) and chemical composition (by solid-state C NMR spectroscopy) to warming in two alpine swamp meadows (Kobresia humilis vs K. tibetica) on the Tibetan Plateau. Our results showed that four years of warming had significant influences on plant belowground biomass, microbial community and SOC contents in the K. humilis swamp meadow, but had much weaker or minor effects in the K. tibetica swamp meadow with water-logged status and lower level of warming. In the K. humilis swamp meadow, warming increased microbial biomass, C-hydrolysis gene abundance and N-acetylglucosaminidase enzyme activity. These positive effects of warming on microbial biomass and functions further increased soil dissolved inorganic nitrogen and alleviated the nitrogen limitation for plant growth, potentially leading to higher plant biomass. Therefore, increases in SOC and particulate organic carbon (POC) under warming were likely attributed to the higher C input with promoted plant biomass overweighting the simultaneous higher C degradation and release in the K. humilis swamp meadow. Conversely, warming marginally reduced soil alkyl C, which was likely associated with enhanced decomposition by fungi and gram-positive bacteria. Overall, the increases in unprotected POC and decreases in recalcitrant alkyl C demonstrate the sensitivity of SOC physical fractions as well as chemical composition to climate warming in the K. humilis alpine swamp meadow, and suggest that the overall stability of SOC might be lower despite the gain in the content of SOC after climate warming in this alpine swamp meadow.
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http://dx.doi.org/10.1016/j.scitotenv.2021.148072DOI Listing
October 2021

Apatinib Plus Gefitinib as First-Line Treatment in Advanced EGFR-Mutant NSCLC: The Phase III ACTIVE Study (CTONG1706).

J Thorac Oncol 2021 09 24;16(9):1533-1546. Epub 2021 May 24.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China. Electronic address:

Introduction: Blocking vascular endothelial growth factor pathway can enhance the efficacy of EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC. ACTIVE is the first phase 3 study conducted in the People's Republic of China evaluating apatinib, a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, plus gefitinib as first-line therapy in EGFR-mutant NSCLC.

Methods: Treatment-naive patients with stage IIIB or IV nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and EGFR exon 19 deletion or exon 21 L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/d), plus apatinib (500 mg/d; apatinib [A] + gefitinib [G] group), or placebo (placebo [P] + gefitinib [G] group). Stratification factors were mutation type, sex, and performance status. The primary end point was progression-free survival (PFS) by blinded independent radiology review committee (IRRC). Secondary end points were investigator-assessed PFS, overall survival, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance.

Results: A total of 313 patients were assigned to the A + G (n = 157) or P + G group (n = 156). Median IRRC PFS in the A + G group was 13.7 months versus 10.2 months in the P + G group (hazard ratio 0.71, p = 0.0189). Investigator- and IRRC-assessed PFS were similar. Overall survival was immature. The most common treatment-emergent adverse events greater than or equal to grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A + G group and increased alanine aminotransferase (10.4%) and aspartate aminotransferase (3.2%) in the P + G group. QoL in the two groups had no statistical differences. Post hoc analysis revealed PFS benefits tended to favor the A + G group in patients with TP53 exon 8 mutation.

Conclusions: Apatinib + gefitinib as first-line therapy had superior PFS in advanced EGFR-mutant NSCLC versus placebo + gefitinib. Combination therapy brought more adverse events but did not interfere QoL.

Trial Registration: NCT02824458.
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http://dx.doi.org/10.1016/j.jtho.2021.05.006DOI Listing
September 2021

Production of viable chicken by allogeneic transplantation of primordial germ cells induced from somatic cells.

Nat Commun 2021 05 20;12(1):2989. Epub 2021 May 20.

Key Laboratory of Animal Breeding Reproduction and Molecular Design for Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, China.

The allogeneic transplantation of primordial germ cells (PGCs) derived from somatic cells overcomes the limitation of avian cloning. Here, we transdifferentiate chicken embryo fibroblasts (CEFs) from black feathered Langshan chickens to PGCs and transplant them into White Plymouth Rock chicken embryos to produce viable offspring with characteristics inherited from the donor. We express Oct4/Sox2/Nanog/Lin28A (OSNL) to reprogram CEFs to induced pluripotent stem cells (iPSCs), which are further induced to differentiate into PGCs by BMP4/BMP8b/EGF. DNA demethylation, histone acetylation and glycolytic activation elevate the iPSC induction efficiency, while histone acetylation and glycolytic inhibition facilitate PGCs formation. The induced PGCs (iPGCs) are transplanted into the recipients, which are self-crossed to produce 189/509 somatic cells derived chicken with the donor's characteristics. Microsatellite analysis and genome sequencing confirm the inheritance of genetic information from the donor. Thus, we demonstrate the feasibility of avian cloning from somatic cells.
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http://dx.doi.org/10.1038/s41467-021-23242-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138025PMC
May 2021

Inorganic-organic competitive coating strategy derived uniform hollow gradient-structured ferroferric oxide-carbon nanospheres for ultra-fast and long-term lithium-ion battery.

Nat Commun 2021 May 20;12(1):2973. Epub 2021 May 20.

Department of Chemistry, Shanghai Key Lab of Molecular Catalysis and Innovative Materials, and Laboratory of Advanced Materials, Fudan University, Shanghai, P. R. China.

The gradient-structure is ideal nanostructure for conversion-type anodes with drastic volume change. Here, we demonstrate an inorganic-organic competitive coating strategy for constructing gradient-structured ferroferric oxide-carbon nanospheres, in which the deposition of ferroferric oxide nanoparticles and polymerization of carbonaceous species are competitive and well controlled by the reaction thermodynamics. The synthesized gradient-structure with a uniform size of ~420 nm consists of the ferroferric oxide nanoparticles (4-8 nm) in carbon matrix, which are aggregated into the inner layer (~15 nm) with high-to-low component distribution from inside to out, and an amorphous carbon layer (~20 nm). As an anode material, the volume change of the gradient-structured ferroferric oxide-carbon nanospheres can be limited to ~22% with ~7% radial expansion, thus resulting in stable reversible specific capacities of ~750 mAh g after ultra-long cycling of 10,000 cycles under ultra-fast rate of 10 A g. This unique inorganic-organic competitive coating strategy bring inspiration for nanostructure design of functional materials in energy storage.
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http://dx.doi.org/10.1038/s41467-021-23150-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137936PMC
May 2021

Quantitative imaging of intracellular nanoparticle exposure enables prediction of nanotherapeutic efficacy.

Nat Commun 2021 04 22;12(1):2385. Epub 2021 Apr 22.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.

Nanoparticle internalisation is crucial for the precise delivery of drug/genes to its intracellular targets. Conventional quantification strategies can provide the overall profiling of nanoparticle biodistribution, but fail to unambiguously differentiate the intracellularly bioavailable particles from those in tumour intravascular and extracellular microenvironment. Herein, we develop a binary ratiometric nanoreporter (BiRN) that can specifically convert subtle pH variations involved in the endocytic events into digitised signal output, enabling the accurately quantifying of cellular internalisation without introducing extracellular contributions. Using BiRN technology, we find only 10.7-28.2% of accumulated nanoparticles are internalised into intracellular compartments with high heterogeneity within and between different tumour types. We demonstrate the therapeutic responses of nanomedicines are successfully predicted based on intracellular nanoparticle exposure rather than the overall accumulation in tumour mass. This nonlinear optical nanotechnology offers a valuable imaging tool to evaluate the tumour targeting of new nanomedicines and stratify patients for personalised cancer therapy.
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http://dx.doi.org/10.1038/s41467-021-22678-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062465PMC
April 2021

Iguratimod ameliorates nephritis by modulating the Th17/Treg paradigm in pristane-induced lupus.

Int Immunopharmacol 2021 Jul 31;96:107563. Epub 2021 Mar 31.

Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Electronic address:

Objective: Iguratimod, an anti-rheumatic drug, has been widely used in the treatment of rheumatoid arthritis, but is still at an investigative stage for treatment of systemic lupus erythematosus (SLE). We examined the therapeutic effects of iguratimod and the mechanism underlying the efficacy in murine lupus model.

Methods: Pristane-induced lupus model of BALB/c mice (PI mice) were treated with iguratimod and mycophenolate mofetil. Proteinuria, anti-dsDNA antibodies and immunoglobulins production were measured. Renal pathology was evaluated. The percentage of Th17 and Treg cells in spleen and the expression of cytokines and mRNAs related to Th17 and Treg cells was analyzed.

Results: Iguratimod attenuated the severity of nephritis in PI mice in a dose-dependent manner. Proteinuria was continuously decreased and pathology of glomerulonephritis and tubulonephritis was significantly reduced along with reduction of glomerular immune complex deposition. Also, serum anti-dsDNA and total IgG and IgM levels were reduced by iguratimod in mice. It is worth mentioning that the efficacy of the 30 mg/kg/d iguratimod dose is comparable to, or even better than, 100 mg kg/d of mycophenolate mofetil. Furthermore, the percentage of Th17 cells was found decreased and the percentage of Treg cells increased. ROR-γt mRNA and serum cytokines (IL-17A and IL-22) of Th17 cells decreased accordingly. By contrast, Foxp3 mRNA and cytokines (TGF-β and IL-10) of Treg cells increased.

Conclusion: Iguratimod ameliorates nephritis of SLE and modulates the Th17/Treg ratio in murine nephritis of SLE, suggesting that Iguratimod could be an effective drug in treatment of SLE.
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http://dx.doi.org/10.1016/j.intimp.2021.107563DOI Listing
July 2021

Spin1z induces the male pathway in the chicken by down-regulating Tcf4.

Gene 2021 May 22;780:145521. Epub 2021 Feb 22.

Key Laboratory of Animal Breeding Reproduction and Molecular Design for Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China. Electronic address:

SPINDLIN1-Z (SPIN1Z), a member of the Spin/Ssty(Y-linked spermiogenesis specific transcript) protein family, participates in the early embryonic development process. Our previous RNA-seq analysis indicates that the level of Spin1z was abundantly expressed in male embryonic stem cells (ESCs) and primitive germ cells (PGCs), we speculate that Spin1z may play an important role in chicken male differentiation. Therefore, the loss- and gain-of-function experiments provide solid evidence that Spin1z is both necessary and sufficient to initiate male development in chicken. Furthermore, chromatin immunoprecipitation (ChIP) assay and the dual-luciferase assay was performed to further confirm that Spin1z contributed to chicken male differentiation by inhibiting the Tcf4 transcription. Our findings provide a novel insight into the molecular mechanism for chicken male differentiation.
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http://dx.doi.org/10.1016/j.gene.2021.145521DOI Listing
May 2021

Genome-Scale CRISPR-Cas9 Transcriptional Activation Screening in Metformin Resistance Related Gene of Prostate Cancer.

Front Cell Dev Biol 2020 26;8:616332. Epub 2021 Jan 26.

Department of Urology, Huizhou Municipal Central Hospital, Huizhou, China.

Metformin is a classic type II diabetes drug which possesses anti-tumor properties for various cancers. However, different cancers do not respond to metformin with the same effectiveness or acquire resistance. Thus, searching for vulnerabilities of metformin-resistant prostate cancer is a promising strategy to improve the therapeutic efficiency of the drug. A genome-scale CRISPR-Cas9 activation library search targeting 23,430 genes was conducted to identify the genes that confer resistance to metformin in prostate cancer cells. Candidate genes were selected by total reads of sgRNA and sgRNA diversity, and then a CCK8 assay was used to verify their resistance to metformin. Interestingly, we discovered that the activation of ECE1, ABCA12, BPY2, EEF1A1, RAD9A, and NIPSNAP1 contributed to resistance to metformin in DU145 and PC3 cell lines. Notably, a high level of RAD9A, with poor prognosis in PCa, was the most significant gene in the CCK8 assay. Furthermore, we discerned the tumor immune microenvironment with RAD9A expression by CIBERSORT. These results suggested that a high level of RAD9A may upregulate regulatory T cells to counterbalance metformin in the tumor immune microenvironment.
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http://dx.doi.org/10.3389/fcell.2020.616332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870801PMC
January 2021

Glycolysis Combined with Core Pluripotency Factors to Promote the Formation of Chicken Induced Pluripotent Stem Cells.

Animals (Basel) 2021 Feb 6;11(2). Epub 2021 Feb 6.

Key Laboratory of Animal Breeding Reproduction and Molecular Design for Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) in vitro. Previously, a lentivirus induction strategy of introducing Oct4, Sox2, Nanog and Lin28 (OSNL) into the iPSC process has been shown as a possible way to produce chicken iPSCs from chicken embryonic fibroblasts, but the induction efficiency of this method was found to be significantly limiting. In order to help resolve this efficiency obstacle, this study seeks to clarify the associated regulation mechanisms and optimizes the reprogramming strategy of chicken iPSCs. This study showed that glycolysis and the expression of glycolysis-related genes correlate with a more efficient reprogramming process. At the same time, the transcription factors Oct4, Sox2 and Nanog were found to activate the expression of glycolysis-related genes. In addition, we introduced two small-molecule inhibitors (2i-SP) as a "glycolysis activator" together with the OSNL cocktail, and found that this significantly improved the induction efficiency of the iPSC process. As such, the study identifies direct molecular connections between core pluripotency factors and glycolysis during the chicken iPSC induction process and, with its results, provides a theoretical basis and technical support for chicken somatic reprogramming.
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http://dx.doi.org/10.3390/ani11020425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915628PMC
February 2021

Long Noncoding RNA Mediated by TCF7L2 Regulates Primordial Germ Cell Formation in Chickens.

Animals (Basel) 2021 Jan 24;11(2). Epub 2021 Jan 24.

Key Laboratory of Animal Breeding Reproduction and Molecular Design for Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, Jiangsu, China.

Although lncRNAs have been identified as playing critical roles in the development of germ cells, their potential involvement in the development of PGCs in chickens remains poorly understood. Differentially expressed lncRNAs (DELs) from previous RNA-seq of embryonic stem cells (ESCs), PGCs, and spermatogonial stem cells (SSCs) were analyzed by K-means clustering, from which a key candidate, lncRNA (lncRNA PGC regulator, ) was obtained. We confirmed that plays a positive role in the development of PGCs by increasing the expression of the PGC marker gene ( and ), while downregulating the pluripotency-associated gene () in vitro and in vivo. The activation and expression of are regulated by histone acetylation, and transcription factor TCF7L2. Mechanistically, a rescue assay was performed to further confirm that contributed to the development of PGCs by regulating the gga-miR-6577-5p/ signaling pathway. Adsorption of gga-miR-6577-5p activated the WNT signaling cascade by relieving the gga-miR-6577-5p-dependent inhibition of expression. Taken together, our study discovered the growth-expedited role of in PGCs development, showing the potential /miR-6577-5p/ pathway. The results and findings provide a novel insight into the development of PGCs.
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http://dx.doi.org/10.3390/ani11020292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912682PMC
January 2021

Functions of CD169 positive macrophages in human diseases (Review).

Biomed Rep 2021 Feb 17;14(2):26. Epub 2020 Dec 17.

Department of Cell Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.

CD169 macrophages are a unique type of macrophage subset that differ from M1 and M2 macrophages. CD169 macrophages are present in multiple tissues and organs throughout the body and are primarily expressed in secondary lymphoid organs. These cells are primarily divided across three locations in secondary lymphoid organs: The metallophilic marginal zone of the spleen, the subcapsular sinus and the medulla of the lymph nodes. Due to their unique location distribution and the presence of the CD169 molecule on their surfaces, CD169 macrophages are reported to serve important roles in several processes, such as phagocytosis, antigen presentation, immune tolerance, viral infection and inflammatory responses. At the same time, it has been reported that CD169 macrophages may also serve an important role in anti-tumour immunity. The present review focuses on the research progress surrounding the function of CD169 macrophages in a variety of diseases, such as viral infection, autoimmune diseases and tumours.
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http://dx.doi.org/10.3892/br.2020.1402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780751PMC
February 2021

CircRNA DNA methyltransferase 1 silence inhibits breast cancer development by regulating micoRNA-485-3p/zinc finger E-box binding homeobox 1 axis.

J Obstet Gynaecol Res 2021 Mar 5;47(3):1068-1081. Epub 2021 Jan 5.

Department of Radiotherapy, Jiangxi Cancer Hospital, Nanchang, China.

Background: Circular RNAs (circRNAs) are associated with tumorigenesis of breast cancer. Nevertheless, how and whether circRNA DNA methyltransferase 1 (circ-DNMT1) controls breast cancer development remains poorly understood.

Methods: The paired tumor and paracancer tissues (n = 41) were obtained from breast cancer patients. Circ-DNMT1, microRNA (miR)-485-3p, and zinc finger E-box binding homeobox 1 (ZEB1) abundances were measured by quantitative reverse transcription polymerase chain reaction and western blot. Cell colony formation, migration, invasion, and apoptosis were analyzed by colony formation analysis, transwell analysis, and flow cytometry. Target relationship was evaluated via dual-luciferase reporter analysis, RNA immunoprecipitation, and pull-down. The in vivo experiments were conducted using a xenograft model.

Results: Circ-DNMT1 and ZEB1 levels were upregulated in breast cancer, and miR-485-3p was downregulated. Circ-DNMT1 knockdown restrained cell colony formation, migration, and invasion and increased apoptosis. MiR-485-3p was negatively regulated by circ-DNMT1, and miR-485-3p knockdown mitigated the effect of circ-DNMT1 silence on breast cancer development. ZEB1 was targeted via miR-485-3p, miR-485-3p overexpression repressed cell colony formation, migration, and invasion and triggered apoptosis by decreasing ZEB1. Circ-DNMT1 silence reduced ZEB1 expression via regulating miR-485-3p. Circ-DNMT1 knockdown reduced xenograft tumor growth.

Conclusion: Circ-DNMT1 knockdown constrains breast cancer development via modulating miR-485-3p/ZEB1 axis.
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http://dx.doi.org/10.1111/jog.14639DOI Listing
March 2021

Circular RNA RBM33 contributes to cervical cancer progression via modulation of the miR-758-3p/PUM2 axis.

J Mol Histol 2021 Apr 5;52(2):173-185. Epub 2021 Jan 5.

Department of Obstetrics & Gynaecology, the Affiliated Jintan Hospital of Jiangsu University, Changzhou, 213200, People's Republic of China.

Cervical cancer (CC) is a gynecological malignant tumor. Circular RNA (hsa_circ_0001772) (circRBM33) is implicated in the tumorigenesis of cancers. Nevertheless, the role of circRBM33 in CC is indistinct. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to evaluate the levels of circRBM33, miR-758-3p, and pumilio RNA binding family member 2 (PUM2) mRNA in tissue samples and cells. Cell proliferation, apoptosis, migration, invasion, and glycolysis were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, flow cytometry assay, transwell assay, or special commercial kits. Relative protein levels were examined via western blotting. The targeting relationship between circRBM33 or PUM2 and miR-758-3p was verified via dual-luciferase reporter or RNA pull-down assays. The role of circRBM33 was confirmed via tumor formation experiments. CircRPPH1 and PUM2 were upregulated while miR-758-3p was downregulated in CC tissues and cells. Functionally, circRBM33 knockdown constrained tumor growth in vivo and cured CC cell proliferation, migration, invasion, glycolysis, and fostered CC cell apoptosis in in vitro. Mechanistically, circRBM33 sponged miR-758-3p to modulate PUM2 expression. MiR-758-3p inhibitor neutralized circRBM33 silencing-mediated effects on the malignant behaviors of CC cells. PUM2 elevation overturned the suppressive influence of miR-758-3p upregulation on the malignant behaviors of CC cells. CircRBM33 fostered CC advancement via absorbing miR-758-3p and upregulating PUM2, indicating that circRBM33 was a possible target for CC treatment.
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http://dx.doi.org/10.1007/s10735-020-09933-1DOI Listing
April 2021

A Binary Cre Transgenic Approach Dissects Microglia and CNS Border-Associated Macrophages.

Immunity 2021 01 16;54(1):176-190.e7. Epub 2020 Dec 16.

Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

The developmental and molecular heterogeneity of tissue macrophages is unravelling, as are their diverse contributions to physiology and pathophysiology. Moreover, also given tissues harbor macrophages in discrete anatomic locations. Functional contributions of specific cell populations can in mice be dissected using Cre recombinase-mediated mutagenesis. However, single promoter-based Cre models show limited specificity for cell types. Focusing on macrophages in the brain, we establish here a binary transgenic system involving complementation-competent NCre and CCre fragments whose expression is driven by distinct promoters: Sall1: Cxcr1 mice specifically target parenchymal microglia and compound transgenic Lyve1: Cxcr1 animals target vasculature-associated macrophages, in the brain, as well as other tissues. We imaged the respective cell populations and retrieved their specific translatomes using the RiboTag in order to define them and analyze their differential responses to a challenge. Collectively, we establish the value of binary transgenesis to dissect tissue macrophage compartments and their functions.
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http://dx.doi.org/10.1016/j.immuni.2020.11.007DOI Listing
January 2021

Neutrophil to Lymphocyte Ratio Predicts Outcome of Stroke by Cervicocranial Arterial Dissection.

Front Med (Lausanne) 2020 27;7:598055. Epub 2020 Nov 27.

Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.

Neutrophil to lymphocyte ratio (NLR) is positively associated with poor prognosis in patients with cerebral infarction. The goal of this prospective study is to explore the predictive value of NLR in patients with acute ischemic stroke (AIS) caused by cervicocranial arterial dissection (CCAD). Ninety-nine patients with AIS caused by CCAD met criteria for inclusion and exclusion were selected for this study. We collected baseline data on the admission including NLR. The primary poor outcome was major disability (modified Rankin Scale score ≥ 3) or death at 3 months after AIS. A total of 20 (20.2%) patients had a poor outcome at 3 months after AIS. According to the 3-month outcome, the patients were divided into two groups and univariate and multivariable analyses were conducted. Among the risk factors, elevated NLR levels were independently associated with 3-month poor outcomes. Further, we made the ROC curve to evaluate the predictive value of NLR level on prognosis. The area under the curve was 0.79 and a cut-off value of NLR was 2.97 for differentiating the poor outcome. We divided patients into groups according to the cut-off value. Patients with high NLR have a higher risk of poor outcome than those with low NLR ( < 0.05). As an inflammatory marker, elevated NLR levels were associated with 3-month poor outcome in AIS caused by CCAD.
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http://dx.doi.org/10.3389/fmed.2020.598055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729127PMC
November 2020

LncRNA MIR4435-2HG mediates cisplatin resistance in HCT116 cells by regulating Nrf2 and HO-1.

PLoS One 2020 24;15(11):e0223035. Epub 2020 Nov 24.

Department of Tumor Radiotherapy of Jiangxi Province Cancer Hospital, Nanchang, Jiangxi, China.

Purpose: Cisplatin resistance is still a serious problem in the clinic. However, the underlying mechanism remains unknown. In our study, we investigated cisplatin resistance by using the cisplatin-resistant cell line HCT116R.

Methods: The HCT116 cell line, a colon cancer cell line, was purchased. Cell viability was determined using CCK-8 Assay Kit. The gene expression levels of MIR4435-2HG, Nrf2, and HO-1, and caspase activity were determined using qRT-PCR and Caspase 3 Assay Kit, respectively.

Results: In this study, we found that the levels of the lncRNA MIR4435-2HG were dramatically increased in the cisplatin-resistant cell line HCT116R. Knockdown of MIR4435-2HG in HCT116R cells significantly restored the sensitivity to cisplatin, inhibited cell proliferation and promoted cell apoptosis. Furthermore, Nrf2 and HO-1 mRNA levels, as critical molecules in the oxidative stress pathway, were inhibited by siRNAs targeting MIR4435-2HG, suggesting that MIR4435-2HG-mediated cisplatin resistance occurs through the Nrf2/HO-1 pathway.

Conclusion: Our findings demonstrate that the lncRNA MIR4435-2HG is a main factor driving the cisplatin resistance of HCT116 cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223035PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685444PMC
December 2020

Design, synthesis, and bioimaging applications of a new class of carborhodamines.

Analyst 2021 Jan;146(1):64-68

School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China.

We herein developed a new class of carborhodamines (CRs), i.e. 10-methoxy-substituted carborhodamines MCRs, by a simple synthesis procedure, which have absorption and emission wavelengths longer than classical CRs while retaining their excellent photophysical properties. Based on the MCR platform, we constructed the mitochondria-targeted fluorescent probe MCR-DMA and demonstrated its potential for sensing singlet oxygen (1O2) in living cells during the photodynamic therapy process.
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http://dx.doi.org/10.1039/d0an01916jDOI Listing
January 2021

Global analysis and optimal harvesting for a hybrid stochastic phytoplankton-zooplankton-fish model with distributed delays.

Math Biosci Eng 2020 09;17(5):6149-6180

School of Mathematical Sciences, Chongqing Normal University, Chongqing 401131, China.

In this paper, we formulate a phytoplankton-zooplankton-fish model with distributed delays and hybrid stochastic noises involving Brownian motion and Markov chain, and propose an optimal harvesting problem pursuing the maximum of total economic income. By global analysis in terms of some system parameters, we investigate the dynamical behaviors on the well-posedness, bounded- ness, persistence, extinction, stability and attractiveness of the solutions for the stochastic delayed system. Moreover, we provide sufficient and necessary condition ensuring the existence of the optimization solution for the optimization problem and obtain the optimal harvesting effect and the maximum of sustainable yield. Lastly, two numerical examples and their simulations are given to illustrate the effectiveness of our results.
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http://dx.doi.org/10.3934/mbe.2020326DOI Listing
September 2020

Comparison of the effects of three cryoprotectants on the cryopreservation of mouse subcutaneous tissue under different conditions.

Exp Ther Med 2020 Oct 29;20(4):3285-3289. Epub 2020 Jul 29.

College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China.

The subcutaneous tissue of animals contains different cell types, and different cells have different requirements for cryopreservation. This establishes obstacles that need to be overcome in the clinical application of tissue preservation. In the present study, the effects of different freezing rates and various concentrations of cryoprotectants on the cryopreservation of subcutaneous tissue of mice were compared, and these results provided basic research data that can be used to explore the optimal cryopreservation method for tissue. The effects of three cryoprotectants, dimethyl sulfoxide, glycerinum and 1,2-propanediol, and their concentrations on the cryopreservation of subcutaneous tissue of mice were compared with slow and rapid freezing rates. The results revealed that under various cryopreservation conditions, the percentage of fibroblasts that grow from the tissue following slow cryopreservation (19.8%) was significantly higher than that following rapid freezing (6.7%) at osmotic equilibrium for 10-20 min (P<0.05). After 19 days of culture, under the conditions of slow freezing, with 10, 20 and 30% glycerinum as a cryoprotectant, respectively, fibroblasts grew from 26.0, 16.7 and 16.7% of the tissues, respectively. No fibroblasts were indicated in the tissue mass cultured in any other tissue blocks treated with cryopreservation solutions. Under the condition of rapid freezing, fibroblasts grew from 6.7 and 6.7% tissue blocks of 20% DMSO and 10% glycerinum, respectively, following 19 days of culture. No fibroblasts were identified in the tissue mass cultured in the other tissue blocks treated with cryopreservation solutions, and no fibroblasts were identified in the tissue blocks without osmotic balance before freezing.
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http://dx.doi.org/10.3892/etm.2020.9076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444325PMC
October 2020

Ribbon Synapses and Hearing Impairment in Mice After in utero Sevoflurane Exposure.

Drug Des Devel Ther 2020 8;14:2685-2693. Epub 2020 Jul 8.

Department of Anesthesiology, Shanghai Eye, Ear, Nose, and Throat Hospital, Fudan University, Shanghai 200031, People's Republic of China.

Introduction: In utero, exposure to sevoflurane (a commonly used inhalation anesthetic) can lead to hearing impairment in offspring mice, but the underlying impairment mechanism is not known.

Materials And Methods: Day-15 pregnant mice were treated with 2.5% sevoflurane for 2 h to investigate sevoflurane ototoxicity. Cochleae from offspring mice were harvested for hair-cell and ribbon-synapse assessments. Hearing in offspring mice was assessed at postnatal day 30 using an auditory brainstem-response (ABR) test. Cochlear-explant cultures from offspring mice were exposed to 2.5% sevoflurane for 6 h. Immediately after treatment, explants were assessed for hair-cell morphology, mitochondrial oxidative stress, and autophagy.

Results: In utero, sevoflurane exposure impaired hearing in the offspring is demonstrated by a decrease in ABR wave I amplitudes, a marker for ribbon-synapse functionality. Sevoflurane exposure caused no obvious damage to hair cells, but cochlear ribbon synapses were reduced in postnatal day 15 offspring, and partially recovered by postnatal day 30. Sevoflurane treatment also increased mitochondrial reactive-oxygen species stress and decreased autophagy in the cochlear explants.

Conclusion: These results suggest that oxidative stress and reduced autophagy may underly ribbon-synapse involvement in sevoflurane-induced hearing loss.
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http://dx.doi.org/10.2147/DDDT.S253031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354911PMC
June 2021

Narrow H3K4me2 is required for chicken PGC formation.

J Cell Physiol 2021 02 4;236(2):1391-1400. Epub 2020 Aug 4.

Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Key Laboratory of Animal Breeding Reproduction and Molecular Design for Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, China.

The development of primordial germ cells (PGCs) undergoes epigenetic modifications. The study of histone methylation in regulating PGCs is beneficial to understand the development and differentiation mechanism of germ stem cells. Notably, it provides a theoretical basis for directed induction and mass acquisition in vitro. However, little is known about the regulation of PGC formation by histone methylation. Here, we found the high enrichment of H3K4me2 in the blastoderm, genital ridges, and testis. Chromatin immunoprecipitation sequencing was performed and the results revealed that genomic H3K4me2 is dynamic in embryonic stem cells, PGCs, and spermatogonial stem cells. This trend was consistent with the H3K4me2 enrichment in the gene promoter region. Additionally, narrow region triggered PGC-related genes (Bmp4, Wnt5a, and Tcf7l2) and signaling pathways (Wnt and transforming growth factor-β). After knocking down histone methylase Mll2 in vitro and vivo, the level of H3K4me2 decreased, inhibiting Cvh and Blimp1 expression, then repressing the formation of PGCs. Taken together, our study revealed the whole genome map of H3K4me2 in the formation of PGCs, contributing to improve the epigenetic study in PGC formation and providing materials for bird gene editing and rescue of endangered birds.
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http://dx.doi.org/10.1002/jcp.29945DOI Listing
February 2021

Pharmacokinetics of T0901317 in mouse serum and tissues using a validated UFLC-IT-TOF/MS method.

J Pharm Biomed Anal 2020 Sep 15;189:113420. Epub 2020 Jun 15.

Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, 210009, China; Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

T0901317, a liver X receptors (LXRs) agonist with high-affinity, is widely used to explore the functions of LXRs in various diseases such as atherosclerosis and Alzheimer's disease. However, there is currently little information available about the pharmacokinetics (PK) behavior of T0901317. Here we established a novel ultrafast liquid chromatography-high resolution mass spectrometry method to quantify the concentration of T0901317 in serum, liver, and brain. The chromatographic separation was attained on a C18 (2.1 × 100 mm, 1.8 μm) column using acetonitrile and 0.1 % of formic acid in water as mobile phase operated in gradient elution mode. The mass detection was carried out using negative ions m/z 479.9809 and 322.0882 for T0901317 and internal standard, respectively. The proposed method was fully validated according to the FDA guidelines, and it generally provides good results in terms of linearity (r > 0.99), precision (RSD < 18 % and 12 % for LLOQ and other QC levels, respectively), accuracy (between 92.30 % and 108.16 %), and matrix effect (between 86.56 % and 113.81 %). We then for the first time determined and computed the PK parameters of T0901317 in mouse after intraperitoneal administration of a 20 mg/kg dosage. The peak times (T) in serum, liver, and brain were 1.5, 1.5, and 4 h, respectively, while the half-lives (t) were 4.9, 3.3, and 4.5 h, respectively. Taken together, our results provide a significant choice to study the PK property of T0901317, from which the design of the dosing and sampling protocols of LXRs receptor-antagonist experiments employing T0901317 can also benefit.
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http://dx.doi.org/10.1016/j.jpba.2020.113420DOI Listing
September 2020
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