Publications by authors named "Bin Wu"

2,096 Publications

  • Page 1 of 1

Ordered assembly of the cytosolic RNA-sensing MDA5-MAVS signaling complex via binding to unanchored K63-linked poly-ubiquitin chains.

Immunity 2021 Oct;54(10):2218-2230.e5

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China. Electronic address:

The RNA sensor MDA5 recruits the signaling adaptor MAVS to initiate type I interferon signaling and downstream antiviral responses, a process that requires K63-linked polyubiquitin chains. Here, we examined the mechanisms whereby K63-polyUb chain regulate MDA5 activation. Only long unanchored K63-polyUb (n ≥ 8) could mediate tetramerization of the caspase activation and recruitment domains of MDA5 (CARDs). Cryoelectron microscopy structures of a polyUb-bound CARDs tetramer and a polyUb-bound CARDs-CARD assembly revealed a tower-like formation, wherein eight Ubs tethered along the outer rim of the helical shell, bridging CARDs and CARD tetramers into proximity. ATP binding and hydrolysis promoted the stabilization of RNA-bound MDA5 prior to MAVS activation via allosteric effects on CARDs-polyUb complex. Abundant ATP prevented basal activation of apo MDA5. Our findings reveal the ordered assembly of a MDA5 signaling complex competent to recruit and activate MAVS and highlight differences with RIG-I in terms of CARD orientation and Ub sensing that suggest different abilities to induce antiviral responses.
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http://dx.doi.org/10.1016/j.immuni.2021.09.008DOI Listing
October 2021

LncRNA LINC00115 facilitates lung cancer progression through miR-607/ITGB1 pathway.

Environ Toxicol 2021 Oct 13. Epub 2021 Oct 13.

Pulmonary and Critical Care Medicine, The People's Hospital of Long hua, Shenzhen, China.

Dysregulated long noncoding RNAs (lncRNAs) have potential roles in various cancer types. The objective of this study was to investigate the expression and the underlying role of long intergenic nonprotein coding RNA 115 (LINC00115) in lung cancer. The relative expression of LINC00115 and miR-607 in tumor tissues and cells was detected by real-time PCR. After overexpression or knockdown of LINC00115 expression in tumor cells, the changes in the proliferation, migration, and invasion capacities were detected via Counting Kit-8 (CCK-8) assay and transwell assays. The interplay among LINC00115, miR-607, and integrin β1 (ITGB1) was confirmed by bioinformatics analyses and luciferase reporter assay. In addition, tumor cells with LINC00115 knockdown were injected into nude mice to investigate the effect of LINC00115 on tumorigenesis in vivo. LINC00115 was highly expressed in tumor tissues and cells. LINC00115 promoted the malignant properties of tumor cells. Investigation to its molecular mechanism revealed that LINC00115 functioned as a competitive endogenous RNA (ceRNA), regulating the expression of ITGB1 by sponging miR-607 to affect tumor growth. The LINC00115/miR-607/ITGB1 signaling axis might be a novel therapeutic target in lung cancer.
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http://dx.doi.org/10.1002/tox.23367DOI Listing
October 2021

Identification and Characterization of a Thermostable GH36 α-Galactosidase from WMF1 and Its Application in Synthesizing Isofloridoside by Reverse Hydrolysis.

Int J Mol Sci 2021 Oct 5;22(19). Epub 2021 Oct 5.

College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 Puzhunan Road, Nanjing 211816, China.

An α-galactosidase-producing strain named WMF1, which catalyzed the reverse hydrolysis of d-galactose and glycerol to produce isofloridoside, was isolated from soil. The α-galactosidase (galV) gene was cloned and expressed in . The galV was classified into the GH36 family with a molecular mass of 80 kDa. The optimum pH and temperature of galV was pH 7.5 and 60 °C, respectively, and it was highly stable at alkaline pH (6.0-9.0) and temperature below 65 °C. The specificity for p-nitrophenyl α-d-galactopyranoside was 70 U/mg, much higher than that for raffinose and stachyose. Among the metals and reagents tested, galV showed tolerance in the presence of various organic solvents. The kinetic parameters of the enzyme towards p-nitrophenyl α-d-galactopyranoside were obtained as (0.12 mM), (1.10 × 10 mM s), and (763.92 mM s). During the reaction of reverse hydrolysis, the enzyme exhibited high specificity towards the glycosyl donor galactose and acceptors glycerol, ethanol and ethylene glycol. Finally, the isofloridoside was synthesized using galactose as the donor and glycerol as the acceptor with a 26.6% conversion rate of galactose. This study indicated that galV might provide a potential enzyme source in producing isofloridoside because of its high thermal stability and activity.
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http://dx.doi.org/10.3390/ijms221910778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509150PMC
October 2021

Algorithm for real-time defect detection of micro pipe inner surface.

Authors:
Xinyu Zhao Bin Wu

Appl Opt 2021 Oct;60(29):9167-9179

Quantitative analysis and identification of unknown shaped defects have always been difficult and challenging in the quality control of micro pipes. A series of algorithms for defect detection and feature recognition is presented in this study. A lightweight convolution neural network (LCNN) is introduced to realize defect discrimination. A shallow segmentation network is employed to cooperate with LCNN to obtain pixel-wise crack detection, and a feature recognition algorithm for quantitative measurement is presented. The experimental results show that the proposed algorithms can achieve defect detection with an accuracy of 98.5%, segmentation with mean intersection over union of 0.834, and latency of only 0.2 s. It can be used for online feature recognition and defect detection of the inner surface of a hole.
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http://dx.doi.org/10.1364/AO.438287DOI Listing
October 2021

Ranging system based on optical carrier-based microwave interferometry.

Appl Opt 2021 Oct;60(29):9095-9100

To compensate for the refractive index errors in optical carrier-based microwave interferometry (OCMI), a ranging system is designed to measure the single-arm optical path of OCMI. A high-speed photodetector and a downconversion method are used to acquire the microwave envelope of the interference signal. A Hilbert transformation is used to realize phase detection. Simulation shows the linear relationship between the phase and optical length in a period. Adjusting the microwave frequency can resolve the phase ambiguity. The experimental results show that when the maximum microwave modulation frequency is set to 1.5 GHz, the standard deviation of the measured data can be limited to the level of 10.
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http://dx.doi.org/10.1364/AO.438767DOI Listing
October 2021

848 kHz repetition-rate narrowband dissipative soliton ps-pulsed Figure-9 fiber laser.

Opt Express 2021 Jul;29(15):23967-23975

In this paper, we study the limitations of decreasing the repetition rate for the narrowband dissipative soliton picosecond (ps) pulsed Figure-9 fiber laser with periodically saturable absorber (SA), and demonstrate how to decrease the repetition rate of this kind of fiber laser. By asymmetrically increasing the passive fiber length of nonlinear amplifying loop mirror (NALM) to lower SA saturation power, Q-switching instability can be avoided, thus effectively reducing the repetition rate of ps pulses. To combat noise-like pulse caused by excessive reduction of SA saturation power, we invoke the non-reciprocal output characteristics of periodic SA, and combined with increasing the intracavity fiber length outside the SA, we further reduce the laser repetition rate. Repetition rates for ∼10 and ∼20 ps pulses are reduced to 1.7 MHz and 848 kHz, respectively, which are, to the best of our knowledge, the lowest repetition rates of Figure-9 lasers reported thus far.
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http://dx.doi.org/10.1364/OE.432955DOI Listing
July 2021

Registration of 3D point clouds using a local descriptor based on grid point normal.

Appl Opt 2021 Oct;60(28):8818-8828

The coarse-to-fine method is the prime technology for point cloud registration in 3D reconstruction. Aimed at the problem of low accuracy of coarse registration for the partially overlapping point clouds, a novel, to the best of our knowledge, 3D local feature descriptor named grid normals deviation angles statistics (GNDAS) for aligning roughly pairwise point clouds is proposed in this paper. The descriptor is designed by first dividing evenly the local surface into some grids along the axis and axis of the local reference frame, then making the statistics of the deviation angles of normals at grid points. Based on the correspondences generated by matching descriptors and a transformation estimation method, the initial registration result is obtained. The coarse registration result is used as the initial value of the iterative closest point algorithm to achieve the refinement of the registration result. Experimental comparisons on two public datasets demonstrate that our GNDAS descriptor has high descriptiveness and strong robustness to noise at low level and varying mesh resolution. The registration results also confirm the superiority of our registration approach over previous versions in accuracy and efficiency.
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http://dx.doi.org/10.1364/AO.437477DOI Listing
October 2021

Metrological traceability method for atomic absolute gravimeters.

Appl Opt 2021 Sep;60(26):7910-7920

Cold atomic gravimeters are attracting more and more attention and activity in the area of gravity measurement and comparison, and the corresponding methods for measurement and traceability need to be explored. Based on two self-developed cold atomic gravimeters, research on the comparison and traceability methods of absolute gravity measurement was carried out. The entire gravity measurement traceability process is divided into two stages: the preliminary traceability in the laboratory and the formal traceability in the absolute gravity reference station. Through comparison of two atomic gravimeters (ZAG-E and ZAG-B) in the laboratory, the degree of equivalence and the normalized deviation of ZAG-E are obtained, which are -2.7±7.6µ (=2) and -0.3599, respectively. Relative to the absolute gravity reference at the National Institute of Metrology (NIM) in China, and of ZAG-E are 0.5±12.0µ (=2) and 0.0417, respectively. ||≤1 in the two traceability stages, so the results of two traceability stages are acceptable, which indicates the consistency of the comparisons is good. Finally, the absolute gravity measurement value of ZAG-E is traced to the SI units, ensuring its accuracy. A gravity traceability method for atomic gravimeters is given and is very beneficial for the applications of atomic gravimeters in metrology and other fields.
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http://dx.doi.org/10.1364/AO.430370DOI Listing
September 2021

Patient-Derived Organoids Can Guide Personalized-Therapies for Patients with Advanced Breast Cancer.

Adv Sci (Weinh) 2021 Oct 4:e2101176. Epub 2021 Oct 4.

Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, China.

Most breast cancers at an advanced stage exhibit an aggressive nature, and there is a lack of effective anticancer options. Herein, the development of patient-derived organoids (PDOs) is described as a real-time platform to explore the feasibility of tailored treatment for refractory breast cancers. PDOs are successfully generated from breast cancer tissues, including heavily treated specimens. The microtubule-targeting drug-sensitive response signatures of PDOs predict improved distant relapse-free survival for invasive breast cancers treated with adjuvant chemotherapy. It is further demonstrated that PDO pharmaco-phenotyping reflects the previous treatment responses of the corresponding patients. Finally, as clinical case studies, all patients who receive at least one drug predicate to be sensitive by PDOs achieve good responses. Altogether, the PDO model is developed as an effective platform for evaluating patient-specific drug sensitivity in vitro, which can guide personal treatment decisions for breast cancer patients at terminal stage.
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http://dx.doi.org/10.1002/advs.202101176DOI Listing
October 2021

Sequence- and structure-guided improvement of the catalytic performance of a GH11 family xylanase from Bacillus subtilis.

J Biol Chem 2021 Sep 30:101262. Epub 2021 Sep 30.

School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Brisbane QLD 4072, Australia.

Xylanases produce xylooligosaccharides (XOS) from xylan and have thus attracted increasing attention for their usefulness in industrial applications. Previously, we demonstrated that the GH11 xylanase XynLC9 from Bacillus subtilis formed xylobiose and xylotriose as major products with negligible production of xylose when digesting corncob-extracted xylan. Here, we aimed to improve the catalytic performance of XynLC9 via protein engineering. Based on sequence and structural comparisons of XynLC9 with the xylanases Xyn2 from Trichoderma reesei and Xyn11A from Thermobifida fusca, we identified the N-terminal residues 5-YWQN-8 in XynLC9 as engineering hotspots and subjected this sequence to site-saturation and iterative mutagenesis. The mutants W6F/Q7H and N8Y possessed a 2.6- and 1.8-fold higher catalytic activity than XynLC9, respectively, and both mutants were also more thermostable. Kinetic measurements suggested that W6F/Q7H and N8Y had lower substrate affinity, but a higher turnover rate (k), which resulted in increased catalytic efficiency compared to wild type XynLC9. Furthermore, the W6F/Q7H mutant displayed a 160% increase in the yield of XOS from corncob-extracted xylan. Molecular dynamics simulations revealed that the W6F/Q7H and N8Y mutations led to an enlarged volume and surface area of the active site cleft, which provided more space for substrate entry and product release, and thus accelerated the catalytic activity of the enzyme. The molecular evolution approach adopted in this study provides the design of a library of sequences that captures a meaning functional diversity in a limited number of protein variants.
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http://dx.doi.org/10.1016/j.jbc.2021.101262DOI Listing
September 2021

Comprehensive Proteomic Analysis of Colon Cancer Tissue Revealed the Reason for the Worse Prognosis of Right-Sided Colon Cancer and Mucinous Colon Cancer at the Protein Level.

Curr Oncol 2021 Sep 15;28(5):3554-3572. Epub 2021 Sep 15.

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.

To clarify the molecular mechanisms underlying the poor prognosis of right-sided and mucinous colon cancer at the proteomic level. A tandem mass tag-proteomics approach was used to identify differentially expressed proteins (DEPs) in colon carcinoma tissues from different locations and with different histological types to reveal the underlying mechanisms of these differences at the protein level. In additional, the DEPs were analyzed using bioinformatics methods. The proteomics profiles among colon cancers with different tumor locations and histological types were dramatically distinguished. In terms of tumor locations, the right-sided carcinoma specific DEPs may promote the tumor progression via activating inflammation, metastasis associated pathways. When referring to histological types, the mucinous colon cancers perhaps increased the invasion and metastasis through distinct mechanisms in different tumor locations. For mucinous cancer located in right-sided colon, the mucinous specific DEPs were mainly associated with ECM-related remodeling and the IL-17 signal pathway. For mucinous cancer located in left-sided colon, the mucinous specific DEPs showed a strong relationship with ACE2/Ang-(1-7)/MasR axis. The proteomics profiles of colon cancers showed distinct differences related to locations and histological types. These results suggested a distinct mechanism underlying the diverse subtypes of colon cancers.
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http://dx.doi.org/10.3390/curroncol28050305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482240PMC
September 2021

Overexpressed lncRNA ROR Promotes the Biological Characteristics of ox-LDL-Induced HUVECs the let-7b-5p/HOXA1 Axis in Atherosclerosis.

Front Cardiovasc Med 2021 13;8:659769. Epub 2021 Sep 13.

Department of Vascular Surgery, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The long non-coding RNA regulator of reprogramming (lncRNA ROR) is involved in atherosclerosis (AS), but the specific mechanism remains unclear. The expressions of lncRNA ROR, let-7b-5p, Homeobox A1 (HOXA1), and apoptosis-associated proteins in the serum of AS patients and human umbilical vein endothelial cells (HUVECs) were determined by quantitative real-time PCR (qRT-PCR) and Western blot. The relationships of lncRNA ROR, let-7b-5p, and HOXA1 were analyzed by Pearson's correlation test. The viability and the migration of HUVECs were measured by Cell Counting Kit-8, wound healing, and Transwell assays. The predicted target gene and the potential binding sites were confirmed by dual-luciferase reporter assay. lncRNA ROR was highly expressed in AS, which promoted the cell viability and migration of HUVECs, while lncRNA ROR silencing produced the opposite results. The expression of let-7b-5p, which bound to lncRNA ROR, was downregulated in AS, indicating that the two genes were negatively correlated. Besides this, let-7b-5p reversed the effects of upregulated lncRNA ROR expression on let-7b-5p expression, cell viability, and migration as well as the expressions of apoptosis-related proteins of ox-LDL-treated HUVECs. HOXA1 was targeted by let-7b-5p and upregulated in AS, with its expression being negatively correlated with let-7b-5p but positively correlated with lncRNA ROR. In ox-LDL-treated HUVECs, overexpressed HOXA1 reversed the effects of let-7b-5p, and HOXA1 silencing reversed the effects of lncRNA ROR. In AS, lncRNA ROR promoted the biological characteristics of oxidation of low-density lipoprotein-induced HUVECs the let-7b-5p/HOXA1 axis.
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http://dx.doi.org/10.3389/fcvm.2021.659769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473629PMC
September 2021

Low Molar Mass Dextran: One-Step Synthesis With Dextransucrase by Site-Directed Mutagenesis and its Potential of Iron-Loading.

Front Bioeng Biotechnol 2021 9;9:747602. Epub 2021 Sep 9.

State Key Laboratory of Materials-Oriented Chemical Engineering, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, China.

Iron dextran is a common anti-anemia drug, and it requires low molar mass dextran as substrate. In this work, we selected 11 amino acid residues in domain A/B of DSR-MΔ2 within a 5-angstrom distance from sucrose for site-directed mutagenesis by molecular docking. Mutation of Q634 did not affect the enzyme catalytic activity, but showed an obvious impact on the ratio of low molecular weight dextran (L-dextran, 3,000-5,000 Da) and relatively higher molecular weight dextran (H-dextran, around 10,000 Da). L-dextran was the main product synthesized by DSR-MΔ2 Q634A, and its average molecular weight was 3,951 Da with a polydispersity index <1.3. The structural characterization of this homopolysaccharide revealed that it was a dextran, with 86.0% α(1→6) and 14.0% α(1→4) glycosidic linkages. Moreover, L-dextran was oxidized with NaOH and chelated with ferric trichloride, and an OL-dextran-iron complex was synthesized with a high iron-loading potential of 33.5% (w/w). Altogether, mutation of amino acids near the sucrose binding site of dextransucrase can affect the chain elongation process, making it possible to modulate dextran size.
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http://dx.doi.org/10.3389/fbioe.2021.747602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458854PMC
September 2021

Comparative Metabolomics Reveals Fungal Conversion of Co-Existing Bacterial Metabolites within a Synthetic - Community.

Mar Drugs 2021 Sep 19;19(9). Epub 2021 Sep 19.

Ocean College, Zhejiang University, Zhoushan 321000, China.

In nature, secondary metabolites have been proven to be the essential communication media between co-occurring microorganisms and to influence their relationship with each other. In this study, we conducted a metabolomics survey of the secondary metabolites of an artificial co-culture related to a hydrothermal vent fungal-bacterial community comprising and and their reciprocal relationship. The fungal strain was found to increase the secretion of notoamides and the compound cyclo(Pro-Trp) produced by the actinomycetes strain was discovered to be the responsible molecule. This led to the hypothesis that the fungi transformed cyclo(Pro-Trp) synthesized by the actinomycetes as the biosynthetic precursors of notoamides in the chemical communication. Further analysis showed sp. WU20 was efficient in transforming amino acids into cyclo(Pro-Trp) and adding tryptophan as well as proline into the chemical communication enhanced the induction of the notoamide accumulation. Thus, we propose that the microbial transformation during the synthetic metabolically-mediated chemical communication might be a promising means of speeding up the discovery of novel bioactive molecules. The objective of this research was to clarify the mechanism of microbial transformation for the chemical communication. Besides, this research also highlights the utility of mass spectrometry-based metabolomics as an effective tool in the direct biochemical analysis of community metabolites.
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http://dx.doi.org/10.3390/md19090526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472691PMC
September 2021

New Antiproliferative Compounds against Glioma Cells from the Marine-Sourced Fungus sp. ZZ1750.

Mar Drugs 2021 Aug 26;19(9). Epub 2021 Aug 26.

Ocean College, Zhejiang University, Zhoushan Campus, Zhoushan 316021, China.

Seven novel compounds, namely peniresorcinosides A-E (-), penidifarnesylin A (), and penipyridinone A (), together with the 11 known ones -, were isolated from a culture of the marine-associated fungus sp. ZZ1750 in rice medium. The structures of the new compounds were established based on their high-resolution electrospray ionization mass spectroscopy (HRESIMS) data, extensive nuclear magnetic resonance (NMR) spectroscopic analyses, chemical degradation, Mosher's method, C-NMR calculations, electronic circular dichroism (ECD) calculations, and single crystal X-ray diffraction. Peniresorcinosides A () and B () are rare glycosylated alkylresorcinols and exhibited potent antiglioma activity, with IC values of 4.0 and 5.6 µM for U87MG cells and 14.1 and 9.8 µM for U251 cells, respectively.
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http://dx.doi.org/10.3390/md19090483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465473PMC
August 2021

Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial.

JAMA Oncol 2021 Sep 23. Epub 2021 Sep 23.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Isocitrate dehydrogenase 1 (IDH1) variations occur in up to approximately 20% of patients with intrahepatic cholangiocarcinoma. In the ClarIDHy trial, progression-free survival as determined by central review was significantly improved with ivosidenib vs placebo.

Objective: To report the final overall survival (OS) results from the ClarIDHy trial, which aimed to demonstrate the efficacy of ivosidenib (AG-120)-a first-in-class, oral, small-molecule inhibitor of mutant IDH1-vs placebo for patients with unresectable or metastatic cholangiocarcinoma with IDH1 mutation.

Design, Setting, And Participants: This multicenter, randomized, double-blind, placebo-controlled, clinical phase 3 trial was conducted from February 20, 2017, to May 31, 2020, at 49 hospitals across 6 countries among patients aged 18 years or older with cholangiocarcinoma with IDH1 mutation whose disease progressed with prior therapy.

Interventions: Patients were randomized 2:1 to receive ivosidenib, 500 mg, once daily or matched placebo. Crossover from placebo to ivosidenib was permitted if patients had disease progression as determined by radiographic findings.

Main Outcomes And Measures: The primary end point was progression-free survival as determined by blinded independent radiology center (reported previously). Overall survival was a key secondary end point. The primary analysis of OS followed the intent-to-treat principle. Other secondary end points included objective response rate, safety and tolerability, and quality of life.

Results: Overall, 187 patients (median age, 62 years [range, 33-83 years]) were randomly assigned to receive ivosidenib (n = 126; 82 women [65%]; median age, 61 years [range, 33-80 years]) or placebo (n = 61; 37 women [61%]; median age, 63 years [range, 40-83 years]); 43 patients crossed over from placebo to ivosidenib. The primary end point of progression-free survival was reported elsewhere. Median OS was 10.3 months (95% CI, 7.8-12.4 months) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1 months) with placebo (hazard ratio, 0.79 [95% CI, 0.56-1.12]; 1-sided P = .09). When adjusted for crossover, median OS with placebo was 5.1 months (95% CI, 3.8-7.6 months; hazard ratio, 0.49 [95% CI, 0.34-0.70]; 1-sided P < .001). The most common grade 3 or higher treatment-emergent adverse event (≥5%) reported in both groups was ascites (11 patients [9%] receiving ivosidenib and 4 patients [7%] receiving placebo). Serious treatment-emergent adverse events considered ivosidenib related were reported in 3 patients (2%). There were no treatment-related deaths. Patients receiving ivosidenib reported no apparent decline in quality of life compared with placebo.

Conclusions And Relevance: This randomized clinical trial found that ivosidenib was well tolerated and resulted in a favorable OS benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation.

Trial Registration: ClinicalTrials.gov Identifier: NCT02989857.
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http://dx.doi.org/10.1001/jamaoncol.2021.3836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461552PMC
September 2021

Association of antibiotics use in preschool age with atopic and allergic skin diseases in young adulthood: a population-based retrospective cohort study.

BMJ Open 2021 Sep 21;11(9):e047768. Epub 2021 Sep 21.

Department of Dermatology; Hunan Engineering Research Center of Skin Health and Disease; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China

Background: Overuse and misuse of antibiotics is a public health problem in low-income and middle-income countries. Although the association of antibiotics with atopic and allergic diseases has been established, most studies focused on prenatal exposure and the occurrence of disease in infants or young children.

Objective: To investigate the association of preschool use of antibiotics with atopic and allergic skin diseases in young adulthood.

Design: Population-based retrospective cohort.

Setting And Participants: The first-year college students (n=20 123) from five universities were investigated. The sampled universities are located in Changsha, Wuhan, Xiamen, Urumqi and Hohhot, respectively.

Methods: We conducted a dermatological field examination and a questionnaire survey inquiring the participants about the frequency of upper respiratory tract infection (URTI) and the preschool antibiotics use (prior to 7 years old). The two-level probit model was used to estimate the associations, and adjusted risk ratio (aRR) and 95% CI were presented as the effect size.

Results: A total of 20 123 participants with complete information was included in the final analysis. The frequent antibiotics use intravenously (aRR 1.36, 95% CI 1.14 to 1.62) and orally (aRR 1.18, 95% CI 1.01 to 1.38) prior to 7 years old was significantly associated with atopic dermatitis in young adulthood. Similar trends could be observed in allergic skin diseases among those who use antibiotics orally and intravenously, with RRs of 1.16 (95% CI 1.01 to 1.34) and 1.33 (95% CI 1.13 to 1.57), respectively.

Conclusions: Preschool URTI and antibiotics use significantly increases the risk of atopic and allergic skin diseases in young adulthood.
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http://dx.doi.org/10.1136/bmjopen-2020-047768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458315PMC
September 2021

Design, synthesis, and biological evaluation of cyano-substituted 2,4-diarylaminopyrimidines as potent JAK3 inhibitors for the treatment of B-cell lymphoma.

Bioorg Chem 2021 Sep 11;116:105330. Epub 2021 Sep 11.

College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address:

A series of cyano-substituted 2,4-diarylaminopyrimidines was designed and synthesized as potent non-covalent JAK3 inhibitors. Among the derivatives synthesized, 9o (IC = 22.86 nM), 9 k (IC = 21.58 nM), and 9j (IC = 20.66 nM) demonstrated inhibitory potencies against JAK3 similar to the known JAK3 inhibitor tofacitinib (IC = 20.10 nM). Moreover, 9o displayed potent anti-proliferative activities against Raji and Ramos cells, with IC values of 0.9255 μM and 1.405 μM, respectively. In addition, 9o demonstrated low toxicity in normal HBE (human bronchial epithelial cells, IC > 10 μΜ) and L-02 (human liver cells, IC = 3.104 μΜ) cells. Analysis of the mode of action by flow cytometry indicated that 9o effectively arrested Raji cells at the G2/M phase. Taken together, these results suggested that 9o might be a promising candidate for development as a potential treatment for B-cell lymphoma.
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http://dx.doi.org/10.1016/j.bioorg.2021.105330DOI Listing
September 2021

The effect of rosuvastatin on cardiogenic cerebral infarction.

Am J Transl Res 2021 15;13(8):9444-9450. Epub 2021 Aug 15.

The First Department of Neurology, Tangshan People's Hospital Tangshan, Hebei Province, China.

Objective: To investigate the effect of rosuvastatin on cardiogenic cerebral infarction and its related effects on patients' neurological function, lipid levels, inflammatory factor levels, and oxidative stress status.

Methods: 300 patients with cardiogenic cerebral infarction were recruited as the study cohort and randomly divided into an observation group and a control group. Routine treatment, including urinary kallikrein injections and bayaspirin tablets were given to the patients in the control group for one month. Rosuvastatin was given once a day in addition to the treatment the control group received to the patients in the observation group, also for one month. The two groups' treatment efficacies were compared. Also, the two groups' NIHSS and mRS scores, lipid and inflammatory factor levels, and their oxidative stress statuses were also compared.

Results: The total effective rate in the observation group was significantly higher than it was in the control group (74.0% vs 84.7%, P=0.023). The NIHSS and mRS scores in the observation group were significantly lower than they were in the control group (all P<0.001). Compared with their levels after the treatment in the control group, the cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels in the observation group were significantly decreased and the high-density lipoprotein cholesterol (HDL-C) was significantly increased (all P<0.001). Moreover, after the treatment, the inflammatory factors, such as the tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) levels, and the oxidative stress status, such as the oxidatively modified low density lipoprotein (ox-LDL) levels, were significantly lower than they were in the control group, but the superoxide dimutase (SOD) levels were significantly higher.

Conclusions: Rosuvastatin remarkably improves the treatment efficacy and neurological function in cardiogenic cerebral infarction patients, and is associated with the improvement of the lipid levels, the inflammatory response, and the oxidative stress status.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430200PMC
August 2021

miRNA-218/FANCI is associated with metastasis and poor prognosis in lung adenocarcinoma: a bioinformatics analysis.

Ann Transl Med 2021 Aug;9(16):1298

Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: In this study, tumor microarray analysis was used to screen the key messenger RNAs (mRNAs) and microRNAs related to the progression of lung adenocarcinoma (LUAD), in order to provide a theoretical basis for early diagnosis, therapeutic targets, and prognosis evaluation of patients with LUAD.

Methods: The mRNA and miRNA expression datasets came from the Gene Expression Omnibus (GEO) project database. Differentially expressed genes (DEGs) and microRNAs (DEMs) between LUAD tissues and adjacent lung tissue were obtained using GEO2R. The Search Tool for the Retrieval of Interacting Genes website was also employed to construct and visualize the interactions of overlapped DEGs. The overall survival of DEMs was investigated using the Kaplan-Meier plotter. The TargetScan website (http://www.targetscan.org/) was used to verify the relationship between FA Complementation Group I (FANCI) and the expression of miRNA-218 (miR-218). The expression of FANCI was verified using the GEO and Human Protein Atlas databases, as well as Real Time Quantitative PCR using our own samples. Next, we analyzed the relationship between the expression of FANCI and the clinicopathological characteristics as well as the prognosis of patients with LUAD. We also explored whether the FANCI was related to immune cell infiltration in LUAD.

Results: FANCI was identified as a hub gene and associated with poor OS. We found that miR-218 negatively regulates FANCI mRNA expression. At the mRNA expression and protein level, FANCI was more highly expressed in LUAD tissues. The expression of FANCI in LUAD was related to tumor size (χ=13.96, P<0.001), lymphatic metastasis (χ=3.88, P<0.05), distant metastasis (χ=45.39, P<0.001), and stage (χ=11.03, P<0.05). In addition, the Cox regression model found that FANCI mRNA expression was an independent predictive factor of patient survival (P<0.05). FANCI expression was both weakly related to B cells and neutrophil infiltration in LUAD.

Conclusions: miR-218 may negatively regulate FANCI, and FANCI could promote metastasis via extracellular matrix (ECM) receptor interaction, leading to poor prognosis of LUAD. FANCI may be a key gene to the determine metastasis and poor prognosis in patients with LUAD. Changes in the immune microenvironment may be the mechanism through which FANCI leads to poor prognosis of LUAD.
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http://dx.doi.org/10.21037/atm-21-3823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422123PMC
August 2021

Effect of lymphadenectomy on the prognosis for N0 gallbladder carcinoma patients: A study based on SEER database.

Cancer Med 2021 Sep 14. Epub 2021 Sep 14.

Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, P.R. China.

Background: It remains unclear whether lymph node dissection is necessary for patients with N0 gallbladder carcinoma (GBC). The objective of this study was to evaluate the effect of lymphadenectomy on the prognosis for N0 GBC patients. The secondary objective was to establish a prognostic model of survival for N0 GBC patients being founded on the large samples.

Methods: Patient data were obtained from the database named SEER (Surveillance, Epidemiology, and End Results database) between 2010 and 2014. Analyses of Kaplan-Meier survival and multivariate Cox regression were performed in subgroups based on regional lymph nodes removal (LNR) to calculate the excess risk of cause-specific death. A prognosis nomogram was constructed build on the results of a multivariate analysis to predict the specific survival time (CSS) rates of N0 GBC patients.

Result: A total of 1406 N0 GBC patients were included in this research. The majority of N0 GBC patients undergoing cancer-directed surgery did not undergo LNR (64.5%). The results showed that LNR can improve the survival of N0 GBC patients, including those at the T1a and T1b stages, and a wider range of lymph node dissection (LNR2) compared to LNR1 was more conducive to the prognosis. Furthermore, multivariate regression analysis showed that LNR was an independent favorable prognostic factor of N0 GBC. Finally, a nomogram was constructed to accurately predict the prognosis of N0 gallbladder cancer patients.

Conclusion: This study demonstrated a significant survival benefit for extended lymph nodes removed in N0 GBC patients. These results recommend that an extended lymph node dissection strategy is needed for N0 GBC patients.
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http://dx.doi.org/10.1002/cam4.4250DOI Listing
September 2021

Increase in Blood-Brain Barrier Permeability is Modulated by Tissue Kallikrein via Activation of Bradykinin B1 and B2 Receptor-Mediated Signaling.

J Inflamm Res 2021 30;14:4283-4297. Epub 2021 Aug 30.

Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China.

Aim: Disruption of the blood-brain barrier (BBB) is a critical pathological feature after stroke. Although tissue kallikrein (TK) has used in the treatment of stroke in China, the role of TK in modulating BBB permeability is not clear.

Methods: We investigated the effect of different doses of TK on BBB by in vivo assessments of Evans blue (EB) and sodium-fluorescein isothiocyanate (FITC) leakage and in vitro assessments of the integrity of BBB and monolayers of microvascular endothelial cells (BMVECs). The expression of zonula occludens-1 (ZO-1) and bradykinin receptor-mediated signaling in BMVECs was detected.

Results: A significant increase in BBB permeability was observed in the mice treated with high dose of TK. However, standard and medium doses of TK could only enable sodium-FITC to enter the brain. The result of in vitro study indicated that high-doses of TK, but not standard and medium-dose of TK, reduced normal BBB integrity accompanied by a decreased expression of zonula occludens-1 (ZO-1), upregulated the mRNA levels of bradykinin 2 receptor (B2R) and endothelial nitric oxide synthase (eNOS) and the abundance of B2R. Moreover, standard-dose of TK exacerbated lipopolysaccharide-induced BBB hyperpermeability, upregulated the mRNA levels of bradykinin 1 receptor (B1R) and inducible nitric oxide synthase (iNOS), increased the abundance of B1R and reduced the abundance of ZO-1; these effects were inhibited by TK inhibitor.

Conclusion: TK can disrupt tight junctions and increase normal BBB permeability via B2R-dependent eNOS signaling pathway, aggravate impairment of BBB via B1R-dependent iNOS signaling pathway, and consequently serve as a useful adjunctive treatment for enhancing the efficacy of other neurotherapeutics.
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http://dx.doi.org/10.2147/JIR.S322225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417820PMC
August 2021

Dihydroartemisinin Induces O-GlcNAcylation and Improves Cognitive Function in a Mouse Model of Tauopathy.

J Alzheimers Dis 2021 Sep 9. Epub 2021 Sep 9.

Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.

Background: Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau pathology. Hyperphosphorylation modification promotes tau protein misfolding and aggregation into neurofibrillary tangles, leading to impairments of synaptic plasticity and learning and memory. However, very limited therapeutic strategies are available.

Objective: In the present study, we wanted to investigate the potential effects of Dihydroartemisinin (DHA) on tauopathies.

Methods: We constructed adeno-associated virus carrying hTau cDNA (AAVhTau) to establish a mouse model of tauopathy through intrahippocampal microinjection. Using a combination of behavioral test, electrophysiological recording, and western blotting assay, we examined the neuroprotective effects of DHA on learning and memory deficits in mice with tauopathy.

Results: DHA improved learning and memory and increased hippocampal CA1 long-term potentiation (LTP) in mice overexpressed human tau (hTau) in the hippocampus. More importantly, further study revealed that DHA could induce protein O-GlcNAcylation modification and reduce protein phosphorylation. O-GlcNAc transferase inhibitor alloxan could suppress DHA-induced protein O-GlcNAcylation, and subsequently prevent therapeutic effect of DHA on the deficits of learning and memory as well as synaptic plasticity in hTau mice.

Conclusion: These results indicate that DHA may exert neuroprotective role in tauopathy through a crosstalk between O-GlcNAcylation and phosphorylation, suggesting a potential therapeutic for learning and memory deficits associated with tau pathology.
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http://dx.doi.org/10.3233/JAD-210643DOI Listing
September 2021

ASPM combined with KIF11 promotes the malignant progression of hepatocellular carcinoma via the Wnt/β-catenin signaling pathway.

Exp Ther Med 2021 Oct 10;22(4):1154. Epub 2021 Aug 10.

Department of Hepatological Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.

To investigate the molecular mechanism of assembly factor for spindle microtubules (ASPM) in the regulation of the malignant progression of hepatocellular carcinoma (HCC), bioinformatics analysis was utilized to analyze the role of ASPM in the malignant progression of HCC and its potential interaction with the kinesin family member 11 (KIF11) gene. The expression levels of ASPM and KIF11 were detected by reverse transcription-quantitative PCR and western blotting. Following knockdown of ASPM expression, Cell Counting Kit-8/colony formation assays were performed to detect cell viability and proliferation. Wound healing and Transwell assays were employed to detect cell migration and invasion. Additionally, a co-immunoprecipitation (CO-IP) assay was used to detect whether there was an interaction between ASPM and KIF11. KIF11 overexpression was performed to verify if ASPM exerted its effects via KIF11. ASPM was highly expressed in HCC tissues and cells, and was closely associated with a poor prognosis of patients with HCC. Interference with ASPM expression markedly inhibited the viability, proliferation, invasion and migration of HCC cells. Using a CO-IP assay, it was revealed that there was an interaction between ASPM and KIF11. Rescue experiments subsequently revealed the regulatory effects of ASPM on the activity, proliferation, invasion and migration of HCC cells via KIF11. Finally, western blot analysis demonstrated that ASPM in combination with KIF11 promoted the malignant progression of HCC by regulating the activity of the Wnt/β-catenin signaling pathway. Therefore, the present study demonstrated that ASPM may interact with KIF11 in HCC cells to promote the malignant progression of HCC via the Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.3892/etm.2021.10588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393588PMC
October 2021

Positive Charges in the Brace Region Facilitate the Membrane Disruption of MLKL-NTR in Necroptosis.

Molecules 2021 Aug 27;26(17). Epub 2021 Aug 27.

State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.

Necroptosis is a type of programmed cell death executed through the plasma membrane disruption by mixed lineage kinase domain-like protein (MLKL). Previous studies have revealed that an N-terminal four-helix bundle domain (NBD) of MLKL is the executioner domain for the membrane permeabilization, which is auto-inhibited by the first brace helix (H6). After necroptosis initiation, this inhibitory brace helix detaches and the NBD can integrate into the membrane, and hence leads to necroptotic cell death. However, how the NBD is released and induces membrane rupture is poorly understood. Here, we reconstituted MLKL into membrane mimetic bicelles and observed the structure disruption and membrane release of the first brace helix that is regulated by negatively charged phospholipids in a dose-dependent manner. Using molecular dynamics simulation we found that the brace region in an isolated, auto-inhibited MLKL becomes intrinsically disordered in solution after 7 ns dynamic motion. Further investigations demonstrated that a cluster of arginines in the C-terminus of MLKL is important for the molecular conformational switch. Functional mutagenesis showed that mutating these arginines to glutamates hindered the membrane disruption of full-length MLKL and thus inhibited the necroptotic cell death. These findings suggest that the brace helix also plays an active role in MLKL regulation, rather than an auto-inhibitory domain.
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http://dx.doi.org/10.3390/molecules26175194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433767PMC
August 2021

Transcriptome Differences in Pig Tracheal Epithelial Cells in Response to Infection.

Front Vet Sci 2021 19;8:682514. Epub 2021 Aug 19.

State Key Laboratory of Agricultural Microbiology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.

generally colonizes mammalian/bird respiratory tracts and mainly causes respiratory disorders in both humans and animals. To date, the effects of infection on the respiratory epithelial barriers and molecules in host respiratory epithelial cells in their response to infection are still not well-known. In this study, we used newborn pig tracheal epithelial (NPTr) cells as an model to investigate the effect of infection on host respiratory epithelial barriers. By detecting the transepithelial electrical resistance (TEER) values of NPTr cells and the expression of several known molecules associated with cell adherens and junctions, we found that infection disrupted the barrier functions of NPTr cells. By performing RNA sequencing (RNA-Seq), we determined 30 differentially expressed genes (DEGs), including the vascular endothelial growth factor A (VEGFA) encoding gene , which participated in biological processes (GO:0034330, GO:0045216, and GO:0098609) closely related to epithelial adhesion and barrier functions. These 30 DEGs participated in 22 significant signaling pathways with a -value < 0.05, including the transforming growth factor (TGF)-beta signaling pathway (KEGG ID: ssc04350), hypoxia-inducible factor 1 (HIF-1) signaling pathway (KEGG ID: ssc04066), epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance (KEGG ID: ssc01521), tumor necrosis factor (TNF) signaling pathway (KEGG ID: ssc04668), and mitogen-activated protein kinase (MAPK) signaling pathway (KEGG ID: ssc04010), which are reported to have roles in contributing to the production of inflammatory factors as well as the regulation of epithelial adhesion and barrier function in other tissues and organisms. The results presented in this study may help improve our understanding of the pathogenesis of .
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http://dx.doi.org/10.3389/fvets.2021.682514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417048PMC
August 2021

Hypoxia-induced DEC1 mediates trophoblast cell proliferation and migration via HIF1α signaling pathway.

Tissue Cell 2021 Aug 12;73:101616. Epub 2021 Aug 12.

Department of Clinical Laboratory Medicine, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. Electronic address:

In early pregnancy, hypoxia is a typical extrinsic factor that regulates EVT functions including proliferation, migration and invasion which are essential for a successful pregnancy. Human differentiated embryonic chondrocyte-expressed gene 1 (DEC1), a hypoxia-regulated gene, has been reported to be overexpressed in several types of cancers. Given that the placenta and the cancer share several similarities with respect to their capacity to proliferate and invade adjacent tissues, we focused on the role of DEC1 on trophoblast function in a physiologically hypoxic environment, which may be associated with unexplained recurrent spontaneous abortion (URSA).In our study, we measured the expression of HIF-1α and DEC1 in first-trimester villi through real-time-PCR (RT-PCR) and immunohistochemical analysis. in vitro, DEC1 expression was downregulated in trophoblast cells via DEC1-specific shRNA plasmid transfection. The expression of DEC1 and HIF-1α was detected via western blotting and RT-PCR analysis. The proliferation and migration of HTR-8/SVneo cells were assayed using CCK-8 and Transwell migration assays, respectively.Our results indicated that the expression of DEC1 was significantly reduced in villi of URSA compared to that in normal pregnant women. in vitro, hypoxia induced the expression of HIF-1ɑ and DEC1 and upregulated proliferation and migration of the HTR-8/SVneo cells. Knockdown of DEC1 inhibited proliferation and migration of HTR-8/SVneo cells exposure to hypoxia. Furthermore, inhibition of HIF1α expression resulted in a significant decrease in DEC1. These findings illustrate that hypoxia-induced DEC1 expression promotes trophoblast cell proliferation and migration through the HIF1α signaling pathway, which plays an important role during placentation.
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http://dx.doi.org/10.1016/j.tice.2021.101616DOI Listing
August 2021

Efficient Ion Sieving in Covalent Organic Framework Membranes with Sub-2-Nanometer Channels.

Adv Mater 2021 Sep 4:e2104404. Epub 2021 Sep 4.

Anhui Provincial Engineering Laboratory of Functional Membrane Materials and Technology, Department of Applied Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230026, P. R. China.

Membranes of sub-2-nanometer channels show high ion transport rates, but it remains a great challenge to design such membranes with desirable ion selectivities for ion separation applications. Here, covalent organic framework (COF) membranes with a channel size of ≈1.4 nm and abundant hydrogen bonding sites, exhibiting efficient ion sieving properties are demonstrated. The COF membranes have high monovalent cation permeation rates of 0.1-0.2 mol m h and extremely low multivalent cation permeabilities, leading to high monovalent over divalent ion selectivities for K /Mg of ≈765, Na /Mg of ≈680, and Li /Mg of ≈217. Experimental measurements and theoretical simulations reveal that the hydrogen bonding interaction between hydrated cations and the COF channel wall governs the high selectivity, and divalent cations transport through the channel needs to overcome higher energy barriers than monovalent cations. These findings provide an effective strategy for developing sub-2-nanometer sized membranes with specific interaction sites for high-efficiency ionic separation.
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http://dx.doi.org/10.1002/adma.202104404DOI Listing
September 2021

Combination of nigericin with cisplatin enhances the inhibitory effect of cisplatin on epithelial ovarian cancer metastasis by inhibiting slug expression via the Wnt/β-catenin signalling pathway.

Oncol Lett 2021 Oct 3;22(4):700. Epub 2021 Aug 3.

Department of Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.

Epithelial ovarian cancer (EOC) is the most lethal cancer among female genital tumours. Standard therapies, including postoperative chemotherapy, exhibit high proportions of recurrence and resistance. Novel therapeutic strategies are combined with chemotherapy. Emerging studies have demonstrated that nigericin, an H, K and Pb ionophore, exhibits promising anticancer activity in various types of malignancy, such as colorectal and epithelial ovarian cancer. Our previous study suggested that nigericin could regulate EOC cell proliferation, migration and invasion, and may be a novel chemotherapy candidate for EOC. However, to the best of our knowledge, the effects of combined therapy with cisplatin, and the associated underlying mechanisms, are not yet fully understood. The present study aimed to clarify the effects of combined chemical therapy with nigericin and cisplatin on EOC cells and to reveal its mechanism. Wound healing, Transwell, cell viability and colony formation assays were used to measure the migration, invasion and proliferation of EOC cells. Western blotting was used to detect protein expression. A slug overexpression lentivirus was used to create a slug overexpression model in SK-OV-3 cells. Small interfering RNA was used to knock down slug expression. Nigericin combined with cisplatin enhanced the inhibitory effects of cisplatin on the migration and colony formation of EOC cells. Nigericin also enhanced the inhibitory effects of cisplatin on the expression levels of MMP7, as well as the inhibitory effects of cisplatin on the expression levels of β-catenin and GSK-3β, indicating that nigericin and cisplatin regulated in the Wnt/β-catenin signalling pathway. When slug was knocked down, the effect of nigericin was weakened. Overexpression of slug could repress the inhibitory effect of nigericin on the Wnt/β-catenin signalling pathway. Furthermore, nigericin inhibited slug expression by enhancing its modification through small ubiquitin-like modifiers (SUMOs; referred to as SUMOylation). Overall, the present results demonstrated that nigericin combined with cisplatin might serve as a novel therapeutic strategy in patients with metastatic EOC because the combined therapy had higher effectiveness than single drug use. The underlying mechanism of combined therapy maybe the enhanced inhibitory effect of slug through its nigericin-induced SUMOylation.
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http://dx.doi.org/10.3892/ol.2021.12961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358618PMC
October 2021

ARRB1 suppresses the activation of hepatic macrophages via modulating endoplasmic reticulum stress in lipopolysaccharide-induced acute liver injury.

Cell Death Discov 2021 Aug 28;7(1):223. Epub 2021 Aug 28.

Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.

Acute liver injury (ALI) caused by multiple inflammatory responses is a monocyte-/macrophage-mediated liver injury that is associated with high morbidity and mortality. Liver macrophage activation is a vital event that triggers ALI. However, the mechanism of liver macrophage activation has not been fully elucidated. This study examined the role of β-arrestin1 (ARRB1) in wild-type (WT) and ARRB1-knockout (ARRB1-KO) mouse models of ALI induced by lipopolysaccharide (LPS), and ARRB1-KO mice exhibited more severe inflammatory injury and liver macrophage activation compared to WT mice. We found that LPS treatment reduced the expression level of ARRB1 in Raw264.7 and THP-1 cell lines, and mouse primary hepatic macrophages. Overexpression of ARRB1 in Raw264.7 and THP-1 cell lines significantly attenuated LPS-induced liver macrophage activation, such as transformation in cell morphology and enhanced expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), while downregulation of ARRB1 by small interfering RNA and ARRB1 deficiency in primary hepatic macrophages both aggravated macrophage activation. Moreover, overexpression of ARRB1 suppressed LPS-induced endoplasmic reticulum (ER) stress in liver macrophages, and inhibition of ER stress impeded excessive hepatic macrophage activation induced by downregulation of ARRB1. Our data demonstrate that ARRB1 relieves LPS-induced ALI through the ER stress pathway to regulate hepatic macrophage activation and that ARRB1 may be a potential therapeutic target for ALI.
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http://dx.doi.org/10.1038/s41420-021-00615-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403172PMC
August 2021
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