Publications by authors named "Ying Zhu"

1,526 Publications

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LAMR1 restricts Zika virus infection by attenuating the envelope protein ubiquitination.

Virulence 2021 12;12(1):1795-1807

State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan China.

Zika virus (ZIKV) infection can cause severe neurological disorders, including Guillain-Barre syndrome and meningoencephalitis in adults and microcephaly in fetuses. Here, we reveal that laminin receptor 1 (LAMR1) is a novel host resistance factor against ZIKV infection. Mechanistically, we found that LAMR1 binds to ZIKV envelope (E) protein its intracellular region and attenuates E protein ubiquitination through recruiting the deubiquitinase eukaryotic translation initiation factor 3 subunit 5 (EIF3S5). We further found that the conserved G282 residue of E protein is essential for its interaction with LAMR1. Moreover, a G282A substitution abolished the binding of E protein to LAMR1 and inhibited LAMR1-mediated E protein deubiquitination. Together, our results indicated that LAMR1 represses ZIKV infection through binding to E protein and attenuating its ubiquitination.
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http://dx.doi.org/10.1080/21505594.2021.1948261DOI Listing
December 2021

Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway.

Nat Commun 2021 07 19;12(1):4391. Epub 2021 Jul 19.

Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.

Acquired heterotopic ossification (HO) is the extraskeletal bone formation after trauma. Various mesenchymal progenitors are reported to participate in ectopic bone formation. Here we induce acquired HO in mice by Achilles tenotomy and observe that conditional knockout (cKO) of fibroblast growth factor receptor 3 (FGFR3) in Col2 cells promote acquired HO development. Lineage tracing studies reveal that Col2 cells adopt fate of lymphatic endothelial cells (LECs) instead of chondrocytes or osteoblasts during HO development. FGFR3 cKO in Prox1 LECs causes even more aggravated HO formation. We further demonstrate that FGFR3 deficiency in LECs leads to decreased local lymphatic formation in a BMPR1a-pSmad1/5-dependent manner, which exacerbates inflammatory levels in the repaired tendon. Local administration of FGF9 in Matrigel inhibits heterotopic bone formation, which is dependent on FGFR3 expression in LECs. Here we uncover Col2 lineage cells as an origin of lymphatic endothelium, which regulates local inflammatory microenvironment after trauma and thus influences HO development via FGFR3-BMPR1a pathway. Activation of FGFR3 in LECs may be a therapeutic strategy to inhibit acquired HO formation via increasing local lymphangiogenesis.
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http://dx.doi.org/10.1038/s41467-021-24643-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289847PMC
July 2021

Natural history and genetic study of LAMA2-related muscular dystrophy in a large Chinese cohort.

Orphanet J Rare Dis 2021 Jul 19;16(1):319. Epub 2021 Jul 19.

Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China.

Background: LAMA2-related muscular dystrophy including LAMA2-related congenital muscular dystrophy (LAMA2-CMD) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by LAMA2 pathogenic variants. We aimed to describe the natural history and establish genotype-phenotype correlations in a large cohort of Chinese patients with LAMA2-related muscular dystrophy.

Methods: Clinical and genetic data of LAMA2-related muscular dystrophy patients enrolled from ten research centers between January 2003 and March 2021 were collected and analyzed.

Results: One hundred and thirty patients (116 LAMA2-CMD and 14 LGMDR23) were included. LAMA2-CMD group had earlier onset than LGMDR23 group. Head control, independent sitting and ambulation were achieved in 76.3%, 92.6% and 18.4% of LAMA2-CMD patients at median ages of 6.0 months (range 2.0-36.0 months), 11.0 months (range 6.0-36.0 months), and 27.0 months (range 18.0-84.0 months), respectively. All LGMDR23 patients achieved independent ambulation at median age of 18.0 months (range 13.0-20.0 months). Motor regression in LAMA2-CMD mainly occurred concurrently with rapid progression of contractures during 6-9 years old. Twenty-four LAMA2-related muscular dystrophy patients died, mostly due to severe pneumonia. Seizures occurred in 35.7% of LGMDR23 and 9.5% of LAMA2-CMD patients. Forty-six novel and 97 known LAMA2 disease-causing variants were identified. The top three high-frequency disease-causing variants in Han Chinese patients were c.7147C > T (p.R2383*), exon 4 deletion, and c.5156_5159del (p.K1719Rfs*5). In LAMA2-CMD, splicing variants tended to be associated with a relatively mild phenotype. Nonsense variants were more frequent in LAMA2-CMD (56.9%, 66/116) than in LGMDR23 (21.4%, 3/14), while missense disease-causing variants were more frequent in LGMDR23 (71.4%, 10/14) than in LAMA2-CMD (12.9%, 15/116). Copy number variations were identified in 26.4% of survivors and 50.0% of nonsurvivors, suggesting that copy number variations were associated with lower rate of survival (p = 0.029).

Conclusions: This study provides better understandings of natural history and genotype-phenotype correlations in LAMA2-related muscular dystrophy, and supports therapeutic targets for future researches.
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http://dx.doi.org/10.1186/s13023-021-01950-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287797PMC
July 2021

Neurological Complications of Veno-Arterial Extracorporeal Membrane Oxygenation: A Retrospective Case-Control Study.

Front Med (Lausanne) 2021 1;8:698242. Epub 2021 Jul 1.

Department of Critical Care Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

To explore the epidemiology, clinical features, risk indicators, and long-term outcomes of neurological complications caused by veno-arterial extracorporeal membrane oxygenation (V-A ECMO). We retrospectively analyzed 60 adult patients who underwent V-A ECMO support in our unit from February 2012 to August 2020. These patients were separated into the neurological complications group (NC group) and the non-neurological complications group (nNC group). The differences in basic data and ECMO data between the two groups were compared. The data of long-term neurological prognosis were collected by telephone follow-up. Thirty-nine patients (65.0%) had neurological complications. There were significant differences between the two groups in terms of median age, hypertension, median blood urea nitrogen, median troponin I (TNI), median lactic acid, pre-ECMO percutaneous coronary intervention, continuous renal replacement therapy (CRRT), median Sequential Organ Failure Assessment score, median Acute Physiology and Chronic Health Evaluation II score, median peak inspiratory pressure, median positive end expiratory pressure, and median fresh frozen plasma ( < 0.05). The median Intensive Care Unit length of stay (ICU LOS), 28-day mortality, median post-ECMO vasoactive inotropic score, non-pulsate perfusion (NP), and median ECMO duration of the NC group were significantly higher than those of the nNC group ( < 0.05). Furthermore, multiple logistic regression analysis revealed that TNI ( = 0.043), CRRT ( = 0.047), and continuous NP > 12 h ( = 0.043) were independent risk indicators for neurological complications in patients undergoing ECMO. Forty-four patients (73.3%) survived after discharge, and 38 patients (63.3%) had Cerebral Performance Category score of 1-2. And there were significant differences between the two groups in long-term neurological outcomes after discharge for 6 months ( < 0.05). The incidence of neurological complications was higher in patients undergoing V-A ECMO and was closely related to adverse outcomes (including ICU LOS and 28-day mortality). TNI, CRRT, and continuous NP > 12 h were independent risk indicators for predicting neurological complications in ECMO supporting patients. And the neurological complications of patients during ECMO support had significant adverse effect on long-term surviving and neurological outcomes of patients after discharge for 6 months.
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http://dx.doi.org/10.3389/fmed.2021.698242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280317PMC
July 2021

Colorectal cancer risk variant rs7017386 modulates two oncogenic lncRNAs expression via ATF1-mediated long-range chromatin loop.

Cancer Lett 2021 Jul 15;518:140-151. Epub 2021 Jul 15.

Department of Epidemiology and Biostatistics, And the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

The activating transcription factor 1 (ATF1) has been identified as a vital pathogenic factor in the progression of colorectal cancer (CRC), whiles, the precise regulatory mechanisms remain elusive. Here, we comprehensively characterized the ATF1 cistrome by RNA-seq and ChIP-seq assays in CRC cell lines. As the results, we identified 358 genes differentially regulated and 15,029 ATF1 binding sites and demonstrated that ATF1 was widely involved in major signaling pathways in CRC, such as Wnt, TNF, Jak-STAT. Subsequently, by the expression quantitative trait loci (eQTL) analyses, we found that rs7017386 was associated with the expression of CCAT1 and PVT1 in the Wnt pathway. By a two-stage population study with 6,131 CRC cases and 10,022 healthy controls, we identified the variant was associated with CRC risk. Mechanistically, we found rs7017386 allele-specifically enhanced the binding affinity of ATF1 and promoted the expressions of PVT1 and CCAT1, via forming a long-range chromatin loop. Moreover, those two lncRNAs could synergistically facilitate c-Myc expression to activate the Wnt pathway in CRC progression. Our findings not only demonstrated the transcriptomic profiling of ATF1 in CRC, but also provided important clues for the etiology of CRC.
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http://dx.doi.org/10.1016/j.canlet.2021.07.021DOI Listing
July 2021

Carbapenemase detection by NG-Test CARBA 5-a rapid immunochromatographic assay in carbapenem-resistant diagnosis.

Ann Transl Med 2021 May;9(9):769

Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: The global spread of carbapenem-resistant (CRE) represents a serious public health concern as these organisms are associated with limited treatment options, high mortality rate and rapid transmissibility. The identification of carbapenemase remains a challenge in microbiological laboratories as no single method is perfect when considering cost, carbapenemase coverage, accuracy, handling complexity and TATs together.

Methods: NG-Test CARBA 5 assay and modified carbapenem inactivation method in conjunction with EDTA carbapenem inactivation method (mCIM/eCIM) were challenged with a collection of 299 molecularly characterized CRE isolates in China in order to evaluate the performance in detecting five major carbapenemases ( , , , , and ) among Enterobacterales.

Results: NG-Test CARBA 5 detected all KPC-, NDM-, VIM- and OXA-48-producing isolates perfectly with a weak false-positive signal for NDM in an IMP-4 producer, which makes the specificity for NDM decreases to 99.6%. The overall specificity/sensitivity were 99.9%/100% for NG-Test CARBA 5. mCIM/eCIM achieved high specificity of 100%/100% and sensitivity of 99.6%/97.4%, with one S. marcescens isolate harboring VIM-2 undetected.

Conclusions: Both NG-Test CARBA 5 and mCIM/eCIM showed excellent results in the tested carbapenemase ( , , , , and ) detection compared with molecular genotypic test. As every assay has its own limitations, suitable methods should be combined for the establishment of the CRE diagnostic pathways.
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http://dx.doi.org/10.21037/atm-20-8216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246204PMC
May 2021

Genetic-algorithm-empowered metasurface design: simultaneous realization of high microwave frequency-selection and low infrared surface-emissivity.

Opt Express 2021 Jun;29(13):20150-20159

With the improvement of equipment integration, it is difficult to meet the increasing functional requirements with the function of a single spectrum. In this work, a multispectral functional metasurface (MFM) is designed to achieve multispectral compatibility between microwave and infrared using multi-optimization. For microwaves, a frequency selective surface (FSS) is designed to achieve frequency selectivity. And for infrared, a twice genetic algorithm (GA) is employed to further increase the metallic filling ratio, thus reducing the infrared emissivity while maintaining the performance of microwave FSS. In order to verify our design and method, the MFM is fabricated and measured, and all the results are consistent with the theoretical design. The performance of FSS can achieve 3dB bandwidth in 7.2-11.2GHz with low insertion losses and stability, and meanwhile the mean infrared emissivity has been reduced to 0.24 in 3-14μm. In summary, the designed multispectral compatible metasurface has wide application value in radome. What's more, the multi-optimization method for designing the multispectral metasurface can also be extended to other fields.
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http://dx.doi.org/10.1364/OE.427492DOI Listing
June 2021

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J Pharmacol Exp Ther 2021 Jul 12. Epub 2021 Jul 12.

Department of Pharmacology, Soochow University, China

Our previous studies have shown that cathepsin L (CTSL) is involved in the ability of tumors to resist ionizing radiation (IR), but the specific mechanisms responsible for this remain unknown. We report here that mutant p53 (mut-p53) is involved in IR-induced transcription of CTSL. We found that irradiation caused activation of CTSL in mut-p53 cell lines whereas there was almost no activation in p53 wild-type (wt-p53) cell lines. Additionally, luciferase reporter gene assay results demonstrated that IR induced the p53 binding region on the CTSL promoter. We further demonstrated that the expression of p300 and Egr-1 was up-regulated in mut-p53 cell lines after IR treatment. Accordingly, the expression of Ac-H3, Ac-H4, AcH3K9 was up-regulated after IR treatment in mut-p53 cell lines, while HDAC4 and HDAC6 were reciprocally decreased. Moreover, knockdown of either Egr-1 or p300 abolished the binding of mut-p53 to the promoter of CTSL. ChIP assay results showed that the IR-activated transcription of CTSL was dependent on p300. To further delineate the clinical relevance of interactions between Egr-1/p300, mut-p53 and CTSL, we accessed primary tumor samples to evaluate the relationships between mut-p53, CTSL and Egr-1 /p300 ex vivo. The results support the notion that mut-p53 is correlated with CTSL transcription involving the Egr-1/p300 pathway. Taken together, the results of our study revealed that p300 is an important target in the process of IR induced transcription of CTSL, which confirms that CTSL participates in mut-p53 gain of function. Transcriptional activation of cathepsin L by ionizing radiation required the involvement of mutated p53 and Egr-1/p300. Interference with Egr-1 or p300 could inhibit the expression of cathepsin L induced by ionizing radiation. The transcriptional activation of cathepsin L by p300 may be mediated by p53 binding sites on the cathepsin L promoter.
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http://dx.doi.org/10.1124/jpet.121.000639DOI Listing
July 2021

Roles of Endogenous Melatonin in Resistance to Infection in an Model.

Front Plant Sci 2021 21;12:683228. Epub 2021 Jun 21.

Provincial Key Laboratory of Biotechnology of Shaanxi, Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, China.

Melatonin is an important bioactive molecule in plants. Two synthetases, N-acetylserotonin methyltransferase (ASMT) and serotonin N-acetyltransferase (SNAT) are involved in the final two steps of melatonin synthesis. Melatonin participates in responses to a variety of biotic and abiotic stresses in plants, but few studies have addressed the roles of endogenous melatonin in pathogen resistance. We investigated the role of endogenous melatonin in resistance to infection in an model system. Plant lines that overexpressed or through genetic manipulation showed upregulated expression of resistance genes and , transcription factor gene , and jasmonic acid (JA) defense pathway marker gene , and downregulated transcription factor gene in JA signaling pathway. Higher melatonin content also enhanced the activity of antioxidant enzymes superoxide dismutase (SOD) and peroxidase (POD), increased JA content, reduced plant disease symptoms, and reduced lesion size in leaves. These findings indicate that endogenous melatonin enhances plant resistance to infection. In contrast, and gene silencing lines showed opposite results and were more susceptible to . Thus, it can be demonstrated that melatonin functions as an effective regulator of plant stress resistance at the genetic level. A schematic model is presented for its role in resistance to infection. Our findings also helped to elucidate the associated signal transduction pathways and interactions between melatonin and other plant hormones.
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http://dx.doi.org/10.3389/fpls.2021.683228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256269PMC
June 2021

Two cases of fatal iatrogenic air embolism confirmed by autopsies.

J Forensic Leg Med 2021 Jun 29;82:102209. Epub 2021 Jun 29.

Department of Forensic Medicine, Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China. Electronic address:

The occurrence of air embolism is highly related to medical operations, and air embolism can cause sudden death. Such situations require attention in forensic work. This article reports two cases of iatrogenic air embolism confirmed by autopsy. In case 1, air embolism occurred after hydrogen peroxide was used to irrigate and disinfect a wound on the patient's left forearm. Approximately 90 ml of 3% hydrogen peroxide solution was used in case 1, and this volume can produce approximately 890 ml of oxygen by complete decomposition, which is far more than the average lethal air embolism volume. Attention should be given to the risk of air embolism when using hydrogen peroxide for irrigation and disinfection. In case 2, air embolism occurred during left ureteroscopy and stent placement. Due to inappropriate processing, the normal saline pump infused air into the patient at a high pressure of 120 mmHg. Based on our autopsy findings, we discuss the pathways of arterial air embolism and cerebral air embolism. In addition to the air entrainment volume and accumulation rate, the location of air accumulation also significantly impacts the risk of air embolism. After an arterial air embolus develops into a coronary and/or cerebral air embolus, the lethal air volume drops to only a few milliliters.
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http://dx.doi.org/10.1016/j.jflm.2021.102209DOI Listing
June 2021

NF-κB is involved in the regulation of autophagy in mutant p53 cells in response to ionizing radiation.

Cell Death Discov 2021 Jun 25;7(1):159. Epub 2021 Jun 25.

Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.

Chemotherapy and ionizing radiation (IR) can induce autophagy in tumor cells. Here, we report that the level of autophagy in tumor cells was related to the background of p53 gene that NF-κB acts as a negative regulator of autophagy in mutant p53 (p53-R273H) cells, and that acetylation was involved in the IR-induced nuclear translocation of NF-κB. We found that autophagy-related proteins were highly expressed in wild-type p53 (wt-p53) cells and that IR increased their levels further. p53-R273H cells exhibited low levels of autophagy; there was no change following IR treatment. The nuclear translocation of p65 was upregulated in p53-R273H cells following IR; when p65 was competitively inhibited from entering the nucleus with SN50, the level of autophagy increased. The nuclear translocation of p65 was mediated by p300; this factor also regulates the nuclear behavior of NF-κB. The knockdown of p300 in p53-R273H cells led to an inhibition of p65 expression and an increase in autophagy. In addition, the inhibition of p300 or p65 not only activated autophagy, it also induced radiosensitivity in p53-R273H cells. The relationship between the p53 gene, NF-κB, and autophagy was further analyzed in a mouse model of xenograft tumors and in clinical tumor pathological specimens; the results were consistent with the in vitro experiments. Our findings indicate that autophagy may be regulated by NF-κB in p53-R273H cells. These findings may help to improve the therapeutic strategy adopted for tumors related to the mutant p53-R273H gene; such therapy would aim to target NF-κB to induce autophagy.
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http://dx.doi.org/10.1038/s41420-021-00533-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257568PMC
June 2021

Detection of Fuchs' Uveitis Syndrome From Slit-Lamp Images Using Deep Convolutional Neural Networks in a Chinese Population.

Front Cell Dev Biol 2021 18;9:684522. Epub 2021 Jun 18.

The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China.

Fuchs' uveitis syndrome (FUS) is one of the most under- or misdiagnosed uveitis entities. Many undiagnosed FUS patients are unnecessarily overtreated with anti-inflammatory drugs, which may lead to serious complications. To offer assistance for ophthalmologists in the screening and diagnosis of FUS, we developed seven deep convolutional neural networks (DCNNs) to detect FUS using slit-lamp images. We also proposed a new optimized model with a mixed "attention" module to improve test accuracy. In the same independent set, we compared the performance between these DCNNs and ophthalmologists in detecting FUS. Seven different network models, including Xception, Resnet50, SE-Resnet50, ResNext50, SE-ResNext50, ST-ResNext50, and SET-ResNext50, were used to predict FUS automatically with the area under the receiver operating characteristic curves (AUCs) that ranged from 0.951 to 0.977. Our proposed SET-ResNext50 model (accuracy = 0.930; Precision = 0.918; Recall = 0.923; F1 measure = 0.920) with an AUC of 0.977 consistently outperformed the other networks and outperformed general ophthalmologists by a large margin. Heat-map visualizations of the SET-ResNext50 were provided to identify the target areas in the slit-lamp images. In conclusion, we confirmed that a trained classification method based on DCNNs achieved high effectiveness in distinguishing FUS from other forms of anterior uveitis. The performance of the DCNNs was better than that of general ophthalmologists and could be of value in the diagnosis of FUS.
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http://dx.doi.org/10.3389/fcell.2021.684522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250145PMC
June 2021

Cytoskeleton-associated protein 2 (CKAP2) is regulated by vascular endothelial growth factor and p53 in retinal capillary endothelial cells under high-glucose conditions.

Mol Cell Endocrinol 2021 Jul 1;535:111378. Epub 2021 Jul 1.

Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address:

Purpose: We previously found the mutation frequency of cytoskeleton-associated protein 2 (CKAP2) was significantly increased in proliferative diabetic retinopathy (PDR) patients through whole exome sequencing. The present study was conducted to explore the expression and possible mechanism of CKAP2 in PDR patients and human retinal capillary endothelial cells (HRCECs) under high-glucose (HG) conditions.

Methods: Expression of CKAP2 and p53 in the vitreous fluid and fibrovascular membrane (FVM) of PDR patients and HRCECs under HG conditions was observed. Cell proliferation, migration and tubule formation were assessed. Ranibizumab and siRNA transfection were used in the inhibition assay.

Results: CKAP2 and p53 were significantly increased in the ocular tissues of PDR patients. HG combined with VEGF treatment significantly up-regulated expression of CKAP2 and p53 in HRCECs. Inhibition of CKAP2 attenuated the abilities of cell proliferation, migration and tube formation under HG conditions. Blocking VEGF or p53 significantly decreased CKAP2 expression, whereas inhibition of CKAP2 failed to alter the level of VEGF or p53.

Conclusions: CKAP2 is involved in the pathogenesis of PDR and regulated by VEGF and p53 under HG conditions.
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http://dx.doi.org/10.1016/j.mce.2021.111378DOI Listing
July 2021

Establishment of epidemiological cut-off values for cefoselis, a new fourth-generation cephalosporin, against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis and Pseudomonas aeruginosa.

J Antimicrob Chemother 2021 Jul 3. Epub 2021 Jul 3.

Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.

Objectives: To establish the epidemiological cut-off values (ECOFFs) for cefoselis against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis and Pseudomonas aeruginosa.

Methods: We collected 2288 non-repetitive clinical isolates from five laboratories throughout four cities in China. The cefoselis MICs and inhibition zone diameters for all isolates were established using the broth microdilution method and the disc diffusion method following EUCAST guidelines. MIC ECOFFs were determined by visual estimation and ECOFFinder software. Zone diameter ECOFFs were set if a high correlation of MICs and inhibition zone diameters was found by Pearson correlation. Zone diameter ECOFFs were finally determined by the visual estimate method.

Results: MICs of cefoselis were distributed from 0.008 to >256 mg/L for the four Enterobacterales species and from 0.25 to >256 mg/L for P. aeruginosa. MIC ECOFFs were 0.125 mg/L for E. coli, K. pneumoniae and P. mirabilis, 0.25 mg/L for E. cloacae and 32 mg/L for P. aeruginosa. A high correlation of MICs and zone diameters was observed for all Enterobacterales (|r| > 0.8, P < 0.001) and a relatively high correlation was found for P. aeruginosa (|r| = 0.71, P < 0.001). The zone diameter ECOFF was 24 mm for E. cloacae, E. coli and K. pneumoniae, 26 mm for P. mirabilis and 21 mm for P. aeruginosa.

Conclusions: We determined MIC and zone diameter ECOFFs for cefoselis against four Enterobacterales species and P. aeruginosa. The establishment of ECOFFs for cefoselis provides clinicians with helpful guidance to differentiate WT and non-WT pathogens.
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http://dx.doi.org/10.1093/jac/dkab216DOI Listing
July 2021

Alteration of gut microbiota in acute pancreatitis and associated therapeutic strategies.

Biomed Pharmacother 2021 Jun 30;141:111850. Epub 2021 Jun 30.

Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 201600, China. Electronic address:

Gut microbiome is considered as a crucial regulator of human health. Alteration of gut microbiome has been reported in acute pancreatitis (AP) and probably contributes to the severity of disease. Explore the precise role of gut microbiome in the pathogenesis of AP could offer new strategies to improve the clinical outcomes of AP. This review summarizes the role of gut microbiome in AP, lists possible mechanisms associated with it and offers an overview of current treatments based on gut microbiome.
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http://dx.doi.org/10.1016/j.biopha.2021.111850DOI Listing
June 2021

[Determination of eight environmental phenols in human urine samples by high-throughput solid-phase extraction-ultra-performance liquid chromatography-tandem mass spectrometry].

Se Pu 2020 Dec;38(12):1456-1464

China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing 100021, China.

A method combining 96-well plate solid-phase extraction with ultra-performance liquid chromatography-tandem mass spectrometry (96-well SPE LC-MS/MS) was developed for the simultaneous determination of eight environmental phenols in urine samples. The samples included seven bisphenol compounds and triclosan. The urine samples were thawed to room temperature, and the target analytes were deconjugated by β -glucuronidase/aryl-sulfatase in ammonium acetate buffer solution at 37℃ overnight. Then, the effects of three kinds of 96-well solid-phase extraction plates and different elution conditions on the purification of the urine samples and the environmental phenol recoveries were compared. The best purification effect was achieved on Oasis HLB 96-well plate (60 mg) solid phase extraction, using 30% (v/v) acetonitrile aqueous solution as the rinse solution. The target analytes were then eluted by methanol solution and evaporated to dryness using a nitrogen blower. After reconstruction with 0.5 mL methanol/water (1:1, v/v) solution, the target compounds were detected by UPLC-MS/MS. To achieve better chromatographic separation, two kinds of analytical columns (C and T3) and different types of mobile phases (methanol and acetonitrile as the organic phase) were also compared. The best chromatographic effect was achieved when the treated samples were separated on a C column (100 mm×2.1 mm, 1.7 μm) using acetonitrile/water as the mobile phase at a flow rate of 0.3 mL/min. Mass spectra were recorded by negative electrospray ionization under the multiple reaction monitoring (MRM) mode. The sample matrix effect was also evaluated. The absolute matrix effects of bisphenol A, bisphenol F, bisphenol S, bisphenol B, and bisphenol AF were in the range of 3.47% to 15.32%. Since the above mentioned matrix effect was weak, there was no need for compensation measures. On the contrary, tetrachlorobisphenol A, tetrabromobisphenol A, and triclosan showed an absolute matrix effect of 49.58% (moderate), 71.99% (strong), and 86.93% (strong), thus necessitating compensation measures. Therefore, this strategy uses a one-to-one corresponding isotope internal standard method to offset the matrix effect. Six different urine samples were used to evaluate the relative matrix effect. The relative standard deviations (RSDs) of the eight corresponding internal standard peak areas were 3.63%-9.06%, indicating that the relative matrix effect was stable. Under the optimized conditions, linearity ranges were 0.50-50 μg/L for bisphenol A and bisphenol AF; 0.05-50 μg/L for tetrachlorobisphenol A and bisphenol S; 0.01-50 μg/L for bisphenol F and tetrabromobisphenol A; 1.00-50 μg/L for bisphenol B; and 5.00-200 μg/L for triclosan. The correlation coefficients were all greater than 0.9995. At spiked levels of 2.5, 5, and 25 μg/L, the average recovery ratios of the eight target analytes were 81.01%-118.84%, while the intra-day and inter-day precisions were 0.38%-19.41% and 2.54%-17.83%, respectively. The limits of detection (LOD) were 0.002-1.09 μg/L, and the limits of quantitation (LOQ) were 0.007-3.63 μg/L. This method was successfully applied to the determination of the eight environmental phenols in 64 urine samples collected from Beijing area between 2019 and 2020. All the target environmental phenols were detected, except for bisphenol B and bisphenol AF. Bisphenol A and bisphenol S showed the highest detection rates of 100% and 96.9%, respectively. The detection rates of triclosan, tetrabromobisphenol A, tetrachlorobisphenol A, and bisphenol F were 57.8%, 46.9%, 23.4%, and 21.9%, respectively. The medium values of urinary concentration followed the order 1.44 μg/L(triclosan), 0.69 μg/L(bisphenol A), 0.086 μg/L (bisphenol S), 0.0032 μg/L (tetrabromobisphenol A), 0.00050 μg/L (tetrachlorobisphenol A), 0.00 μg/L (bisphenol F, bisphenol B, and bisphenol AF). The aforementioned results imply that the widespread environmental phenolic exposure of Beijing residents is worthy of attention. Compared with traditional solid-phase extraction methods, the method reported in this paper is time-saving, effective, and suitable for the simultaneous analysis of large quantities of samples; moreover, the small sample and organic solvent consumption make this method more environment- and operator-friendly.
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http://dx.doi.org/10.3724/SP.J.1123.2020.07021DOI Listing
December 2020

[Determination of polycyclic aromatic hydrocarbon metabolites in urine by liquid-liquid extraction-high resolution gas chromatography-high resolution dual-focus magnetic mass spectrometry].

Se Pu 2020 Jun;38(6):715-721

National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing 100021, China.

A sensitive and accurate method was developed to quantify eight polycyclic aromatic hydrocarbon (PAH) metabolites in human urine by liquid-liquid extraction-high resolution gas chromatography-high resolution dual-focus magnetic mass spectrometry (LLC-HRGC-HRMS). About 2 mL urine was mixed with a deuterium- or C-labeled isotopic internal standard, and the conjugated targets were enzymatically digested in the presence of ascorbic acid. The free compounds were extracted with toluene-pentane (1:4, v/v) and condensed to near dryness. Then, the target compounds were redissolved in toluene. After derivatization, they were separated and quantified by HRGC-HRMS. The linear ranges of the 1-hydroxynaphthalene, 1-hydroxyphenanthrene, and 2-hydroxyphenanthrene were 0.14-41.6 μg/L, 0.05-8.33 μg/L, and 0.04-8.33 μg/L, respectively, and those for the other five PAH metabolites were 0.02-8.33 μg/L. The correlation coefficients were greater than 0.99. The limits of detection were in the range of 0.006-0.042 μg/L, and the recoveries were 81.4%-127.0%. The intra-day and inter-day relative standard deviations (RSDs) were less than 6.9% and 10.9%, respectively. This method was utilized for the determination of 330 human urine samples. The results showed that 3-hydroxychrysene and 6-hydroxychrysene were not detected, and the detection rate of the other six PAH metabolites was 100%. This method is sensitive, accurate and stable, and it is suitable for the determination of the eight PAH metabolites in human urine.
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http://dx.doi.org/10.3724/SP.J.1123.2019.10031DOI Listing
June 2020

Tong Xie Yao Fang: A Classic Chinese Medicine Prescription with Potential for the Treatment of Ulcerative Colitis.

Evid Based Complement Alternat Med 2021 9;2021:5548764. Epub 2021 Jun 9.

Department of Gastroenterology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China.

The prescription of Tong Xie Yao Fang (TXYF) was derived from the Yuan dynasty "Dan Brook Heart Law," which was a representative formula for treating liver-spleen disharmony, diarrhea, and abdominal pain. The prescription is composed of four herbs for soothing the liver and strengthening the spleen. TXYF is reportedly capable of eliminating discomfort in ulcerative colitis (UC). This classic formula has been widely used for regulating gastrointestinal motor dysfunction and repairing colon mucosa. This review aims to provide current information on the pharmacology and clinical research of TXYF in the treatment of UC, and to critically appraise that information, in order to guide the future clinical use and experimental study of TXYF in the treatment of UC. We searched online databases including PubMed, CNKI, and Google Scholar for research published between 2010 and 2020 on TXYF and its efficacy in the treatment of UC. The findings indicated that TXYF has anti-inflammatory and immunomodulatory effects, regulates cell signal transduction, brain-gut axis, and intestinal flora in UC, and may promote targeting of bone mesenchymal stem cells (BMSCs) to the colonic mucosa and accelerate healing of the colonic mucosal barrier. In addition, the results of clinical studies showed that TXYF has good efficacy and few adverse reactions in the treatment of UC. Although it has achieved some success, the research is limited by deficiencies; there is a lack of unified standards for the construction of UC animal models and for administration regimen. In addition, the dosage of TXYF is not consistent and lacks pharmacological verification, and clinical trial data are not detailed or sufficiently rigorous. Therefore, a more rigorous, comprehensive, and in-depth study of TXYF in the treatment of UC is needed.
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http://dx.doi.org/10.1155/2021/5548764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208878PMC
June 2021

Broadening the biocompatibility of gold nanorods from rat to Macaca fascicularis: advancing clinical potential.

J Nanobiotechnology 2021 Jun 30;19(1):195. Epub 2021 Jun 30.

State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.

Background: The biomedical field has used gold nanorods (GNRs) for decades; however, clinical trials and translation is limited except gold nanoshells. The preparation of gold nanoshells is more complex than that of polyethylene glycol-modified GNRs (PEG-GNRs), and it is difficult to ensure uniform thickness. It is important to encourage and broaden the use of the star member (PEG-GNRs) of gold nanoparticles family for clinical translation. Existing studies on PEG-GNRs are limited with no relevant systematic progression in non-human primates. Herein, we assessed the systematic biocompatibility of PEG-GNRs in rats and clinically relevant Macaca fascicularis.

Results: In this small animal study, we administrated multiple doses of PEG-GNRs to rats and observed good biocompatibility. In the non-human primate study, PEG-GNRs had a longer blood half-life and produced a negligible immune response. Histological analysis revealed no significant abnormality.

Conclusions: PEG-GNRs were well-tolerated with good biocompatibility in both small animals and large non-human primates. The information gained from the comprehensive systemic toxicity assessment of PEG-GNRs in M. fascicularis will be helpful for translation to clinical trials.
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http://dx.doi.org/10.1186/s12951-021-00941-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243831PMC
June 2021

Aberrant MCM10 SUMOylation induces genomic instability mediated by a genetic variant associated with survival of esophageal squamous cell carcinoma.

Clin Transl Med 2021 Jun;11(6):e485

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

Background: Esophageal squamous cell carcinoma (ESCC) is one of the common gastrointestinal malignancy with an inferior prognosis outcome. DNA replication licensing aberration induced by dysregulation of minichromosome maintenance proteins (MCMs) causes genomic instability and cancer metastasis. SUMOylation modification plays a pivotal role in regulation of genomic integrity, while its dysregulation fueled by preexisting germline variants in cancers remains poorly understood.

Methods: Firstly, we conducted two-stage survival analysis consisting of an exome-wide association study in 904 ESCC samples and another independent 503 ESCC samples. Then, multipronged functional experiments were performed to illuminate the potential biological mechanisms underlying the promising variants, and MCM10 influences the ESCC progression. Finally, we tested the effects of MCM10 inhibitors on ESCC cells.

Results: A germline variant rs2274110 located at the exon 15 of MCM10 was identified to be significantly associated with the prognosis of ESCC patients. Individuals carrying rs2274110-AA genotypes confer a poor survival (hazard ratio = 1.61, 95% confidence interval = 1.35-1.93, p = 1.35 × 10 ), compared with subjects carrying rs2274110-AG/GG genotypes. Furthermore, we interestingly found that the variant can increase SUMOylation levels at K669 site (Lys[K]699Arg[R]) of MCM10 protein mediated by SUMO2/3 enzymes, which resulted in an aberrant overexpression of MCM10. Mechanistically, aberrant overexpression of MCM10 facilitated the proliferation and metastasis abilities of ESCC cells in vitro and in vivo by inducing DNA over-replication and genomic instability, providing functional evidence to support our population finding that high expression of MCM10 is extensively presented in tumor tissues of ESCC and correlated with inferior survival outcomes of multiple cancer types, including ESCC. Finally, MCM10 inhibitors Suramin and its analogues were revealed to effectively block the metastasis of ESCC cells.

Conclusions: These findings not only demonstrate a potential biological mechanism between aberrant SUMOylation, genomic instability and cancer metastasis, but also provide a promising biomarker aiding in stratifying ESCC individuals with different prognosis, as well as a potential therapeutic target MCM10.
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http://dx.doi.org/10.1002/ctm2.485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236122PMC
June 2021

Thymopentin alleviates premature ovarian failure in mice by activating YY2/Lin28A and inhibiting the expression of let-7 family microRNAs.

Cell Prolif 2021 Jun 28:e13089. Epub 2021 Jun 28.

Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Objective: Thymopentin (5TP) significantly improved typical murine premature ovarian failure (POF) symptoms induced by a high-fat and high-sugar (HFHS) diet. However, its effect and mechanism remain unclear.

Materials And Methods: RNA-Seq was used to detect the differentially expressed genes among each group. HFHS-induced POF mouse model was generated and injected with siRNA using Poly (lactic-co-glycolic acid) (PLGA) as a carrier.

Results: RNA-Seq suggested that 5TP promoted the expression of Yin Yang 2 (YY2) in mouse ovarian granulosa cell (mOGC) of HFHS-POF mice. Luciferase reporter assay indicated that 5TP promoted the binding of YY2 to the specific sequence C(C/T)AT(G/C)(G/T) on the Lin28A promoter and promoted Lin28A transcription and expression. We continuously injected PLGA-cross-linked siRNA nanoparticles targeting YY2 into HFHS-POF mice ([email protected]), which significantly reduced the therapeutic effect of 5TP. [email protected] injection also significantly attenuated the upregulation of Lin28a expression in mOGCs induced by 5TP and enhanced the expression of let-7 family microRNAs, thereby inhibiting the proliferation and division of mOGCs. qPCR results showed that there was a significant difference in the expression levels of exosome-derived Yy2 mRNAs between POF patients and normal women, and that there was a specific correlation between the expression level of exosome-derived Yy2 and the peripheral concentrations of the blood hormones pregnenolone, progesterone and oestradiol.

Conclusions: Thymopentin promotes the transcriptional activation of Lin28A via stimulating transcription factor YY2 expression, inhibits the activity of let-7 family microRNAs and alleviates the ageing of ovarian granulosa cells, ultimately achieving a therapeutic effect on POF in mice.
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http://dx.doi.org/10.1111/cpr.13089DOI Listing
June 2021

Bone morphogenetic protein 4 (BMP4) promotes hepatic glycogen accumulation and reduces glucose level in hepatocytes through mTORC2 signaling pathway.

Genes Dis 2021 Jul 13;8(4):531-544. Epub 2020 Nov 13.

Ministry of Education Key Laboratory of Diagnostic Medicine, Department of Clinical Biochemistry, School of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, PR China.

Liver is an important organ for regulating glucose and lipid metabolism. Recent studies have shown that bone morphogenetic proteins (BMPs) may play important roles in regulating glucose and lipid metabolism. In our previous studies, we demonstrated that BMP4 significantly inhibits hepatic steatosis and lowers serum triglycerides, playing a protective role against the progression of non-alcoholic fatty liver disease (NAFLD). However, the direct impact of BMP4 on hepatic glucose metabolism is poorly understood. Here, we investigated the regulatory roles of BMP4 in hepatic glucose metabolism. Through a comprehensive analysis of the 14 types of BMPs, we found that BMP4 was one of the most potent BMPs in promoting hepatic glycogen accumulation, reducing the level of glucose in hepatocytes and effecting the expression of genes related to glucose metabolism. Mechanistically, we demonstrated that BMP4 reduced the hepatic glucose levels through the activation of mTORC2 signaling pathway and Collectively, our findings strongly suggest that BMP4 may play an essential role in regulating hepatic glucose metabolism. This knowledge should aid us to understand the molecular pathogenesis of NAFLD, and may lead to the development of novel therapeutics by exploiting the inhibitory effects of BMPs on hepatic glucose and lipid metabolism.
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http://dx.doi.org/10.1016/j.gendis.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209350PMC
July 2021

Rapid Body-Wide Transcriptomic Turnover During Rhesus Macaque Perinatal Development.

Front Physiol 2021 10;12:690540. Epub 2021 Jun 10.

School of Life Sciences, Guizhou Normal University, Guiyang, China.

An hourglass cup-shape pattern of regulation at the molecular level was detected during the development of the primate brain. Specifically, a peak of temporally differentially expressed genes around the time of birth has been observed in the human brain. However, to what extend this peak of regulation exists among species has not been investigated in great detail. Here, by integrating multiple large-scale transcriptome data from rhesus macaques, we confirmed that a similar differential expression peak exists during the development of the macaque brain. We also found that a similar peak exists during the development of other organs, such as liver, testis, kidney and heart. Furthermore, we found that distinct pathways are regulated in the peak period of those organs. Our results highlight the importance of co-evolution of diverse organs during critical periods of perinatal development in primates.
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http://dx.doi.org/10.3389/fphys.2021.690540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223001PMC
June 2021

Identifying active sites of boron, nitrogen co-doped carbon materials for the oxygen reduction reaction to hydrogen peroxide.

J Colloid Interface Sci 2021 Jun 14;602:799-809. Epub 2021 Jun 14.

Key Laboratory of Bio-Inspired Smart Interfacial Science and Technology of Ministry of Education, School of Chemistry, Beihang University, Beijing 100191, China; Beijing Advanced Innovation Center for Biomedical Engineering, Beihang University, Beijing 100191, China. Electronic address:

The electrochemical synthesis of hydrogen peroxide (HO) from two-electron oxygen reduction reaction (2e ORR) is a promising alternative for producing chemicals on demand, but its widespread application is still hampered by the low efficiency. Here, we successfully prepared a boron and nitrogen co-doped porous carbon (B/NC) aerogel with a tunable B, N co-doped configuration by the gelation of PVA-graphene, borax and PANI, followed by pyrolysis. Due to a hierarchical porous structure and optimized B, N co-doping, B/NC aerogel showed an excellent electrocatalytic performance for HO production in alkaline solution with a high HO selectivity (94.16%) at positive applied potential (0.6 V vs. RHE), superior than most of the other reported electrocatalysts. Density functional theory (DFT) calculations reveal that the hexagonal boron nitride (hBN) coupled with neighboring pyridinic-N species act as the active sites to lower free energy barrier for formation of HOO* intermediate, thus facilitating HO production. Practically, B 2p electron plays an important role for the adsorption of HOO* intermediates. B and Nco-doping into carbon materials provides an effective and facile method to reasonably construct carbon-based catalysts for electroreduction of O to HO.
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http://dx.doi.org/10.1016/j.jcis.2021.06.068DOI Listing
June 2021

Acetylation-induced PCK isoenzyme transition promotes metabolic adaption of liver cancer to systemic therapy.

Cancer Lett 2021 Jun 21;519:46-62. Epub 2021 Jun 21.

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

Sorafenib and lenvatinib are approved first-line targeted therapies for advanced liver cancer, but most patients develop acquired resistance. Herein, we found that sorafenib induced extensive acetylation changes towards a more energetic metabolic phenotype. Metabolic adaptation was mediated via acetylation of the Lys-491 (K491) residue of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) (PCK2-K491) and Lys-473 (K473) residue of PCK1 (PCK1-K473) by the lysine acetyltransferase 8 (KAT8), resulting in isoenzyme transition from cytoplasmic PCK1 to mitochondrial PCK2. KAT8-catalyzed PCK2 acetylation at K491 impeded lysosomal degradation to increase the level of PCK2 in resistant cells. PCK2 inhibition in sorafenib-resistant cells significantly reversed drug resistance in vitro and in vivo. High levels of PCK2 predicted a shorter progression-free survival time in patients who received sorafenib treatment. Therefore, acetylation-induced isoenzyme transition from PCK1 to PCK2 contributes to resistance to systemic therapeutic drugs in liver cancer. PCK2 may be an emerging target for delaying tumor recurrence.
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http://dx.doi.org/10.1016/j.canlet.2021.06.016DOI Listing
June 2021

Ultrasensitive single-cell proteomics workflow identifies >1000 protein groups per mammalian cell.

Chem Sci 2020 Nov 17;12(3):1001-1006. Epub 2020 Nov 17.

Department of Chemistry and Biochemistry, Brigham Young University Provo UT 84602 USA

We report on the combination of nanodroplet sample preparation, ultra-low-flow nanoLC, high-field asymmetric ion mobility spectrometry (FAIMS), and the latest-generation Orbitrap Eclipse Tribrid mass spectrometer for greatly improved single-cell proteome profiling. FAIMS effectively filtered out singly charged ions for more effective MS analysis of multiply charged peptides, resulting in an average of 1056 protein groups identified from single HeLa cells without MS1-level feature matching. This is 2.3 times more identifications than without FAIMS and a far greater level of proteome coverage for single mammalian cells than has been previously reported for a label-free study. Differential analysis of single microdissected motor neurons and interneurons from human spinal tissue indicated a similar level of proteome coverage, and the two subpopulations of cells were readily differentiated based on single-cell label-free quantification.
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http://dx.doi.org/10.1039/d0sc03636fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178986PMC
November 2020

Husbandry waste derived coralline-like composite biomass material for efficient heavy metal ions removal.

Bioresour Technol 2021 Jun 12;337:125408. Epub 2021 Jun 12.

Advanced Materials Institute, Shandong Academy of Sciences, Qilu University of Technology, Jinan 250014, PR China.

The resource utilization of biological solid waste is crucial for practical environmental remediation. By comprehensively utilizing LiBr treatment and dopamine chemistry, herein the cow dung waste was successfully converted into the composite biomass material for efficient heavy metal ions removal. A selective etching mechanism of cellulose was discovered in the LiBr treatment process, achieving the large-scale preparation of coralline-like porous biomass material with hundred times increased specific surface. Benefiting from the co-deposition of polyethyleneimine and FeO, the fabricated material showed significantly higher adsorption capacity (183.82 and 231.48 mg·g for Cu and Cd) than that of raw cow dung (0.95 and 1.25 mg·g for Cu and Cd). Furthermore, this composite biomass adsorbent also exhibited rapid adsorption equilibrium, magnetic separation capability, monolayer chemisorption feature and feasible recycling use. Collectively, this work contributes to both the resource utilization of husbandry solid waste and the development of advanced biomass adsorbent.
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http://dx.doi.org/10.1016/j.biortech.2021.125408DOI Listing
June 2021

Role of IL-6-IL-27 Complex in Host Antiviral Immune Response.

J Immunol 2021 Jun 18. Epub 2021 Jun 18.

State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China; and

The IL family of cytokines participates in immune response and regulation. We previously found that soluble IL-6 receptor plays an important role in the host antiviral response. In this study, we detected the IL-6-IL-27 complex in serum and throat swab samples from patients infected with influenza A virus. A plasmid expressing the IL-6-IL-27 complex was constructed to explore its biological function. The results indicated that the IL-6-IL-27 complex has a stronger antiviral effect than the individual subunits of IL-6, IL-27A, and EBV-induced gene 3. Furthermore, the activity of the IL-6-IL-27 complex is mainly mediated by the IL-27A subunit and the IL-27 receptor α. The IL-6-IL-27 complex can positively regulate virus-triggered expression of IFN and IFN-stimulated genes by interacting with adaptor protein mitochondrial antiviral signaling protein, potentiating the ubiquitination of TNF receptor-associated factors 3 and 6 and NF-κB nuclear translocation. The secreted IL-6-IL-27 complex can induce the phosphorylation of STAT1 and STAT3 and shows antiviral activity. Our results demonstrate a previously unrecognized mechanism by which IL-6, IL-27A, and EBV-induced gene 3 form a large complex both intracellularly and extracellularly, and this complex acts in the host antiviral response.
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http://dx.doi.org/10.4049/jimmunol.2100179DOI Listing
June 2021

Tetrahedral Framework Nucleic Acid-Based Delivery of Resveratrol Alleviates Insulin Resistance: From Innate to Adaptive Immunity.

Nanomicro Lett 2021 Mar 6;13(1):86. Epub 2021 Mar 6.

State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, P. R. China.

Obesity-induced insulin resistance is the hallmark of metabolic syndrome, and chronic, low-grade tissue inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells. Current therapeutic approaches lack efficacy and immunomodulatory capacity. Thus, a new therapeutic approach is needed to prevent chronic inflammation and alleviate insulin resistance. Here, we synthesized a tetrahedral framework nucleic acid (tFNA) nanoparticle that carried resveratrol (RSV) to inhibit tissue inflammation and improve insulin sensitivity in obese mice. The prepared nanoparticles, namely tFNAs-RSV, possessed the characteristics of simple synthesis, stable properties, good water solubility, and superior biocompatibility. The tFNA-based delivery ameliorated the lability of RSV and enhanced its therapeutic efficacy. In high-fat diet (HFD)-fed mice, the administration of tFNAs-RSV ameliorated insulin resistance by alleviating inflammation status. tFNAs-RSV could reverse M1 phenotype macrophages in tissues to M2 phenotype macrophages. As for adaptive immunity, the prepared nanoparticles could repress the activation of Th1 and Th17 and promote Th2 and Treg, leading to the alleviation of insulin resistance. Furthermore, this study is the first to demonstrate that tFNAs, a nucleic acid material, possess immunomodulatory capacity. Collectively, our findings demonstrate that tFNAs-RSV alleviate insulin resistance and ameliorate inflammation in HFD mice, suggesting that nucleic acid materials or nucleic acid-based delivery systems may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.
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http://dx.doi.org/10.1007/s40820-021-00614-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006527PMC
March 2021

One Stone Four Birds: A Novel Liposomal Delivery System Multi-functionalized with Ginsenoside Rh2 for Tumor Targeting Therapy.

Nanomicro Lett 2020 Jun 16;12(1):129. Epub 2020 Jun 16.

Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, People's Republic of China.

Liposomes hold great potential in anti-cancer drug delivery and the targeting treatment of tumors. However, the clinical therapeutic efficacy of liposomes is still limited by the complexity of tumor microenvironment (TME) and the insufficient accumulation in tumor sites. Meanwhile, the application of cholesterol and polyethylene glycol (PEG), which are usually used to prolong the blood circulation and stabilize the structure of liposomes respectively, has been questioned due to various disadvantages. Herein, we developed a ginsenoside Rh2-based multifunctional liposome system (Rh2-lipo) to effectively address these challenges once for all. Different with the conventional 'wooden' liposomes, Rh2-lipo is a much more brilliant carrier with multiple functions. In Rh2-lipo, both cholesterol and PEG were substituted by Rh2, which works as membrane stabilizer, long-circulating stealther, active targeting ligand, and chemotherapy adjuvant at the same time. Firstly, Rh2 could keep the stability of liposomes and avoid the shortcomings caused by cholesterol. Secondly, Rh2-lipo showed a specifically prolonged circulation behavior in the blood. Thirdly, the accumulation of the liposomes in the tumor was significantly enhanced by the interaction of glucose transporter of tumor cells with Rh2. Fourth, Rh2-lipo could remodel the structure and reverse the immunosuppressive environment in TME. When tested in a 4T1 breast carcinoma xenograft model, the paclitaxel-loaded Rh2-lipo realized high efficient tumor growth suppression. Therefore, Rh2-lipo not only innovatively challenges the position of cholesterol as a liposome component, but also provides another innovative potential system with multiple functions for anti-cancer drug delivery.
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http://dx.doi.org/10.1007/s40820-020-00472-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770862PMC
June 2020